Abuse deterrent opiod/opiod-antagonist transdermal patch

ABSTRACT

The present invention relates to an abuse deterrent transdermal patch.

FIELD OF THE INVENTION

The present invention relates to a transdermal patch. More specifically,the present invention relates to an abuse deterrent transdermal patchfor the transdermal administration of an opioid analgesic. The presentinvention also relates to processes for the preparation of thetransdermal patches defined herein, as well as to the use of thesepatches for the treatment of pain.

BACKGROUND OF THE INVENTION

Opioid analgesics are widely used in the clinic to treat moderate tosevere pain. However, despite their clinical efficacy, opioid analgesicsdo suffer from some major drawbacks. One major drawback is thatprolonged opioid analgesic use can lead to dependence, which gives riseto withdrawal symptoms if the opioid analgesic treatment is stoppedabruptly. This opioid dependence can make opioid analgesics veryaddictive and prone to abuse. In addition, opioid analgesics are alsowell known for their ability to produce a feeling of euphoria,motivating some to use opioids recreationally.

The prevalence of opioid analgesic abuse is a major problem and the Foodand Drug Administration (FDA) in the United States has initiated aprogram to encourage manufacturers of extended release and transdermalopioid formulations to consider innovative strategies to reduce the riskof abuse, and thereby encourage safe opioid use.

The transdermal delivery of opioid analgesics is a convenient andeffective way to deliver opioid analgesics. However, there remains aneed for improved approaches for the transdermal delivery of opioidanalgesics. In addition, there is a need for novel abuse-deterrenttransdermal patches which prevent, or substantially reduce, the risk ofopioid abuse.

Aspects of the invention were devised with the foregoing in mind.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a transdermal patchcomprising a multilaminate, said multilaminate comprising:

(i) a first layer comprising an opioid analgesic compound, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable pressure sensitive adhesive;

(ii) a second layer comprising an opioid antagonist, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable adhesive; and

(iii) a barrier layer disposed between the first and second layers, andwherein the barrier layer substantially prevents the opioid antagonistdiffusing from the second layer to the first layer during use;

wherein a proportion of the opioid antagonist in the second layer ispresent in the form of a pharmaceutically acceptable salt and aproportion of the opioid antagonist is present in a non-salt form (e.g.as a free base).

In a second aspect, the present invention provides a transdermal patchcomprising a multilaminate, said multilaminate comprising:

(i) a first layer comprising an opioid analgesic compound, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable pressure sensitive adhesive;

(ii) a second layer comprising an opioid antagonist, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable adhesive; and

(iii) a barrier layer disposed between the first and second layers, andwherein the barrier layer substantially prevents the opioid antagonistdiffusing from the second layer to the first layer during use;

wherein said barrier layer comprises a material selected from the groupconsisting of polyethylene, ethylene vinyl acetate, polypropylene,polyurethane, polyvinyl acetate, polyvinylidene chloride, polyester,polyethylene terephthalate, polybutylene terephthalate, rayon (synthetictextile fibres produced by forcing cellulose through fine spinnerets andsolidifying the resultant filaments), wood pulp, and spun-lacedpolyester.

The transdermal patches of the present invention are abuse-deterrentpatches. The barrier membrane serves to prevent, or substantiallyprevent, the opioid antagonist present in the second layer frompermeating through to the first layer during normal use of the patch. Asa consequence, little or no opioid antagonist permeates into the skin ofa patient during normal use. If the patch is misused, however, forexample by an individual wishing to extract the opioid analgesic fromthe patch by immersing it in certain solvents, such as water, ethanol oracetone, or by chewing the patch, then the opioid antagonist present inthe second layer will be released in an amount sufficient to antagonisesome or all of the effects of the opioid analgesic that is extracted.This means that the extracted opioid analgesic will not exhibit thepharmacological effects expected.

In order to effectively antagonise the effects of the opioid analgesicreleased from the transdermal patch in certain solvents, it is necessaryfor the ration of opioid analgesic to opioid antagonist to be within acertain range. The range required will depend on the particular opioidanalgesic and antagonist used. Typically, the transdermal patches of thepresent invention release the opioid antagonist at a ratio of 60:1 to1:60 (opioid analgesic : opioid antagonist) when the patch is immersedin water, acetone, ethanol or phosphate buffer (e.g. at a pH of 6-7) fora period of greater than 30 seconds, or greater than 1 minute, orgreater than 2 minutes.

Suitably, the transdermal patches of the present invention release theopioid antagonist at a ratio of 4:1 to 1:4 (opioid analgesic : opioidantagonist) when the patch is immersed in water, acetone, ethanol orphosphate buffer (e.g. at a pH of 6-7) for a period of greater than 30seconds, or greater than 1 minute, or greater than 2 minutes.

More suitably, the transdermal patches of the present invention releasethe opioid antagonist at a ratio of 4:1 to 1:1 (opioid analgesic :opioid antagonist) when the patch is immersed in water, acetone, ethanolor phosphate buffer (e.g. at a pH of 6-7) for a period of greater than30 seconds, or greater than 1 minute, or greater than 2 minutes.

In a third aspect, the present invention provides a transdermal patchcomprising only a first layer as defined herein. Suitably, the opioidanalgesic present in said first layer is oxymorphone, or apharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a transdermal patch asherein defined for use as a medicament or for use in therapy.

In another aspect, the present invention provides a transdermal patch asherein defined for use in the treatment of pain.

In another aspect, the present invention provides a method of treatingpain said method comprising applying a transdermal patch as hereindefined. In another aspect, the present invention provides a method ofpreparing a transdermal patch as defined herein. Suitably, said methodcomprises mixing the components of the first and/or second layersdefined herein respectively and wet casting to form the first and secondlayers defined herein; and assembling the multilaminate by placing abarrier membrane as defined herein between the first and second layers.

DETAILED DESCRIPTION OF THE INVENTION Transdermal Patch of the FirstAspect of the Invention

As indicated above, in a first aspect, the present invention provides atransdermal patch comprising a multilaminate, said multilaminatecomprising:

(i) a first layer comprising an opioid analgesic compound, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable pressure sensitive adhesive;

(ii) a second layer comprising an opioid antagonist, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable adhesive;

(iii) a barrier layer disposed between the first and second layers, andwherein the barrier layer substantially prevents the opioid antagonistdiffusing from the second layer to the first layer during use;

and wherein a proportion of the opioid antagonist in the second layer ispresent in the form of a pharmaceutically acceptable salt and aproportion of the opioid antagonist is present in a non-salt form (e.g.as a free base).

The first layer has a first surface that contacts the barrier membraneand a second opposing surface that contacts the skin during use. Theopioid analgesic present in the first layer diffuses or permeates intothe skin over time to provide the desired analgesic effect.

Similarly, the second layer has a first surface which contacts thebarrier membrane and a second opposing surface.

The barrier membrane prevents or substantially prevents the opioidantagonist present in the second layer from permeating through to thefirst layer during normal use of the patch. As a consequence, little orno opioid antagonist permeates into the skin of a patient during normaluse. If the patch is misused, however, for example by an individualwishing to extract the opioid analgesic from the patch using certainsolvents such as water, ethanol or acetone, or by chewing the patch,then the opioid antagonist present in the second layer will be releasedto antagonise the effects of the opioid analgesic, thereby preventingthe subsequent misuse of the extract opioid analgesic.

The transdermal patch suitably further comprises a backing membrane thatextends over the second layer (i.e. over the second surface of thesecond layer). The second surface of the first layer is suitably coveredwith a peelable release liner that extends across the entire secondsurface of the first layer, but which can be removed to expose thesecond surface of the first layer prior to application of the patch tothe skin.

Backing Membranes

Suitable backing membranes may be occlusive or non-occlusive. Where anon-occlusive backing membrane is used, it is desirable to use a fullyocclusive container or closure system to prevent degradation of the castpharmaceutical formulation layer prior to use. The backing membrane maybe of any thickness, but is suitably between about 10 to 260 μm thick.Suitable materials include, but are not limited to, synthetic polymersincluding, for example, polyesters, polycarbonates, polyimides,polyethylene, poly(ethylene terphthalate), polypropylene, polyurethanesand polyvinylchlorides. The backing membrane may also be a laminatecomprising additional layers that may include vapour deposited metal,such as aluminium, additional synthetic polymers, and other materials,to enable a heat seal, such as EVA copolymer. Suitably, the backingmembrane comprises occlusive Scotchpak 9730® obtainable from 3M.

Release Liner

The release liner is typically disposed on an opposite surface of themulti-laminate (i.e. the second surface of the first layer) to thebacking membrane and provides a removable protective or impermeablelayer, usually but not necessarily rendered non-stick so as to notadhere to the first layer. The release liner serves to protect the firstlayer during storage and transit, and is intended to be removed prior toapplication to the skin. The release liner may be formed from the samematerials used for the backing membrane, but may be formed from metalfoils, Mylar®, polyethylene terephthalate, siliconized polyester, fumedsilica in silicone rubber, polytretrafluoroethylene, cellophane,siliconized paper, aluminized paper, polyvinyl chloride film, compositefoils or films containing polyester such as polyester terephthalate,polyester or aluminized polyester, polytetrafluoroethylene, polyetherblock amide copolymers, polyethylene methyl methacrylate blockcopolymers, polyurethanes, polyvinylidene chloride, nylon, siliconeelastomers, rubber-based polyisobutylene, styrene, styrene-butadiene,and styrene-isoprene copolymers, polyethylene, and polypropylene.

Suitably, the release liner is an occlusive or semi-occlusive backingfilm being compatible with the pharmaceutically-acceptable adhesivepresent in the pharmaceutical formulation layer.

Suitably, the release liner may be selected from Scotchpak 9741®,Scotchpak 1022®, Scotchpak 9742®, Scotchpak 9744®, Scotchpak 9748® andScotchpak 9755®, all of which are obtainable from 3M and comprisefluoropolymers coated onto polypropylene or polyester film. Othersuitable release liners made by other manufacturers may also be used.The release liner may be of any thickness known in the art. Suitably therelease liner has a thickness of about 0.01 mm to about 2 mm.

In one embodiment, the release liner is Scotchpak 9741®. In anotherembodiment, the release liner is Scotchpak 1022®.

The container or closure system may be made from a range of materialssuitable for protecting the packaged transdermal patch from moisture andlight.

The First Layer

In one embodiment, the first layer has a thickness of 0.1-100 mil, moresuitably, 1-50 mil, even more suitably 2-20 mil, and most suitably 5-20mil.

Opioid Analgesic

The first layer of the transdermal patches of the present inventioncomprise an opioid analgesic. Any suitable opioid analgesic may be used.

The opioid analgesic can be selected from the group comprisingalfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, clonitazene, codeine, desomorphine, dextromoramide,dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine,dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl,hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levorphanol, levomethadyl, levophenacylmorphan,lofentanil, meperidine, metazocine, methadone, metopon, morphine,myrophine, narceine, nicomorphine, norlevorphanol, normethadone,normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, promedol, properidine, propoxyphene,sufentanil, tilidine, tramadol, buprenorphine, butorphanol, dezocine,meptazinol, nalbuphine, nalorphine, pentazocine, tapentadol and salts ofthe foregoing. In another embodiment, the composition comprisespharmaceutically acceptable prodrugs of the opioid analgesic.

In an embodiment, the opioid analgesic is selected from morphine,codeine, thebaine, diacetylmorphine (morphine diacetate; heroin),nicomorphine (morphine dinicotinate), dipropanoylmorphine (morphinedipropionate), desomorphine, acetylpropionylmorphine, dibenzoylmorphine,diacetyldihydromorphine, hydromorphone, hydrocodone, oxycodone,oxymorphone, ethylmorphine and buprenorphine, fentanyl, pethidine,levorphanol, methadone, tramadol, tapentadol and dextropropoxyphene.

In a further embodiment, the opioid analgesic is selected frombuprenorphine, fentanyl, hydromorphone, oxycodone, tapentadol oroxymorphone, or a pharmaceutically acceptable salt thereof.

Any suitable opioid containing transdermal formulation may be used toform the first layer in the compositions of the present invention.Examples of suitable first layers for inclusion in the transdermalpatches of the present invention include the fentanyl containingtransdermal formulations described in EP 1381352 B1, U.S. Pat. No.6,139,866, U.S. Pat. No. 5,985,317, U.S. Pat. No. 5,762,952 and U.S.Pat. No. 5,474,783, and tapentadol-containing transdermal formulationsdescribed in WO 2014012653, the entire contents of which areincorporated herein by reference.

In a particular embodiment, the opioid analgesic is oxymorphone, or apharmaceutically acceptable salt thereof.

The amount of opioid analgesic present in the first layer of the patchesof the present invention will depend on how soluble it is in thepharmaceutically-acceptable adhesive and excipients present in thislayer and how much of the opioid is required in order to achieve thedesired therapeutic effect. Typically, the opioid analgesic will bepresent at an amount of 1-10% w/w in the first layer.

In one embodiment, the amount of opioid analgesic present is 3-10% w/win the first layer.

Suitably, the amount of opioid analgesic present is 4-7% w/w, and evenmore suitably 4-6% w/w, in the first layer.

A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic,formic, citric or maleic acid. In addition, a suitable pharmaceuticallyacceptable salt of a compound of the invention which is sufficientlyacidic is an alkali metal salt, for example a sodium or potassium salt,an alkaline earth metal salt, for example a calcium or magnesium salt,an ammonium salt or a salt with an organic base which affords aphysiologically-acceptable cation, for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

Although the opioid analgesic may be present in the form of a salt, aperson skilled in the art will appreciate that the opioid analgesicneeds to be in a form that has a suitable lipophilic/hydrophilic balanceso as to enable good permeation through the skin. In some embodiments ofthe invention, the opioid analgesic is present in a non-salt form, i.e.as a free base or acid.

Pharmaceutically-Acceptable Adhesive

The pharmaceutically-acceptable adhesive present in the first layer isselected both in terms of its ability to solubilise the opioidanalgesic, and its adhesive tack and peel properties.

In one embodiment, the adhesive has an opioid analgesic solubility inexcess of 2.5% w/w at room temperature.

Typically, the total amount of adhesive will constitute between 58 and99% w/w of the first layer.

Any suitable adhesive material or combination of adhesive materials maybe used. Such materials are suitably pressure sensitive adhesives.

Examples of suitable pressure sensitive adhesives include polymer andcopolymers of polyacrylates, polysiloxanes, polyisobutylene,polyisoprene, polybutadiene, ethylene-vinyl acetate and styrenic blockpolymers, such as styrene-isoprene-styrene block copolymer,styrene-butadiene-styrene copolymer, styrene-ethylenebutene-styrenecopolymers, styrene-ethylene/propylene-styrene copolymers and di-blockanalogs thereof. Examples of polyacrylates include, but are not limitedto, acrylic acids, alkyl acrylates and methacrylates; for example,acrylic acid, methacrylic acid, methoxyethyl acrylate, ethyl acrylate,butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate,2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate,isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate,decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecylmethacrylate, tridecyl acrylate, tridecyl methacrylate, hydroxyethylacrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide,acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethylmethacrylate, tert-butylaminoethyl acrylate, tert-butylaminoethylmethacrylate, methoxyethyl acrylate, methoxyethyl methacrylate,vinylacetate/ethylene acrylate and the like. Additional examples ofappropriate acrylic adhesives suitable in the practice of the inventionare described in Satas, “Acrylic Adhesives,” Handbook ofPressure-Sensitive Adhesive Technology, 2nd ed., pp. 396-456 (D. Satas,ed.), Van Nostrand Reinhold, New York (1989).

Other useful pressure sensitive adhesives (PSA) can include mixtures ofdifferent polymers or mixtures of polymers such as synthetic rubberpolyisobutylene (PIB), The PIB adhesives normally include a tackifiersuch as polybutene oil and resins such as the ESCOREZ® resins availablefrom Exxon Chemical. Other useful rubber-based pressure-sensitiveadhesives include hydrocarbon polymers such as natural and syntheticpolyisoprene, polybutylene and polyisobutylene, styrene/butadienepolymers styrene-isoprene-styrene block copolymers, hydrocarbon polymerssuch as butyl rubber, halogen-containing polymers such aspolyacrylic-nitrile, polytetrafluoroethylene, polyvinylchloride,polyvinylidene chloride, and polychlorodiene, and other copolymersthereof. Polyisobutylene polymers are available commercially under thetrademark name VISTANEX® from Exxon Chemical.

Silicone-based pressure sensitive adhesives are also suitable for use inadditional embodiments described herein. Suitable silicone-basedpressure-sensitive adhesives can include those described in Sobieski, etal., “Silicone Pressure Sensitive Adhesives,” Handbook ofPressure-Sensitive Adhesive Technology, 2nd ed., pp. 508-517 (D. Satas,ed.), Van Nostrand Reinhold, New York (1989), incorporated by referencein its entirety. Other useful silicone-based pressure sensitiveadhesives are described in the following U.S. Pat. Nos. 4,591,622;4,584,355; 4,585,836; and 4,655,767 which are hereby incorporated byreference in their entirety. Suitable silicone-based pressure-sensitiveadhesives are commercially available and include the silicone adhesivessold under the trademarks BIO-PSA 7-4503, BIO-PSA 7-4603, BIO-PSA7-4301, 7-4202, 7-4102, 7-4106, and BIO-PSA 7-4303 by Dow CorningCorporation, Medical Products, Midland, Mich. The commercially availablesilicones are sold under the trademark of BIO-PSA such as Bio-PSA7-4102, 7-4202, 7-4302, 7-4101, 7-4201, 7-4301, 7-4303, 7-4503, 7-4603by Dow Corning Cooperation. In one embodiment, amine-compatible Bio-PSAsilicone adhesives are preferred. In a further embodiment, the preferredamine-compatible Bio-PSA silicone adhesive 7-4202 was employed incombination with acrylic adhesive such as Duro-tak 87-9301 manufacturedby National Starch and Chemical Company.

In one embodiment a pressure sensitive adhesive is optionally used toassist in affixing a patch containing an opioid to be transdermallydelivered to the subject. In a further embodiment, the pressuresensitive adhesive is present in a total amount by weight between about58% and about 99%; between about 60% and about 95% and between about 70%and about 90% of the first layer. In a further embodiment the pressuresensitive adhesive layer is a mixture of two or more pressure sensitiveadhesives.

In an embodiment, the adhesive is selected from acrylate/polyacrylatematerials, rubbers and silicones.

In a further embodiment, the adhesive is selected fromacrylate/polyacrylate materials and silicones.

In yet a further embodiment, the adhesive is mixture of anacrylate/polyacrylate material and a silicone material.

Suitably, the silicone adhesive comprises a composition of a siliconeadhesive in a suitable solvent, for example ethyl acetate and/or hexane.As indicated above, examples of such adhesives includes those that arecommercial available from Dow Corning® under the BIOPSA® product range.These adhesives are compatible with amine containing drugs and areformed by a condensation reaction of silanol end-blockedpolydimethylsiloxane (PDMS) with a silicate resin, and the residualsilanol functionality is then capped with trimethylsiloxy groups toyield the chemically stable amine-compatible adhesives.

Particular examples of suitable silicone adhesives include BIO-PSA®7-4502, 7-4302 and 7-4202 or mixtures thereof.

Suitably the silicone based adhesive represents 60-98% w/w of the firstlayer. More suitably, the silicone based adhesive represents 60-90% w/wof the first layer. Even more suitably, the silicone based adhesiverepresents 60-80% w/w of the first layer. Most suitably, the siliconebased adhesive represents 70-80% w/w of the first layer.

Suitably the acrylate or polyacrylate material is an acrylate copolymerand/or an acrylate-vinyl acetate, such as Duro-Tak 87-2677®, Duro-Tak87-900A®, Duro-Tak 87-2074®, Duro-Tak 87-2054®, Duro-Tak 87-2052®,Duro-Tak 87-2196®, Duro-Tak 9301®, Duro-Tak 2054®, Duro-Tak 606A®,and/or Duro-Tak 202A obtainable from Henkel.

In a particular embodiment, the acrylate or polyacrylate material isselected from Duro-Tak 9301®, Duro-Tak 2054®, Duro-Tak 606A®, and/orDuro-Tak 202A®.

In a further embodiment, the acrylate or polyacrylate material isDuro-Tak 9301®.

The amount of the acrylate or polyacrylate material present may bewithin the range of 0 to 98% w/w of the first layer.

Suitably, the acrylate or polyacrylate material is present in additionto the silicone adhesive at the amounts specified above. In suchembodiments, the amount of the acrylate or polyacrylate material presentis within the range of 1-15% w/w of the first layer. In furtherembodiments, where the acrylate or polyacrylate material is present inaddition to the silicone adhesive at the amounts specified above, theamount of the acrylate or polyacrylate material present is within therange of 3-12% w/w of the first layer, or 5 to 12% w/w of the firstlayer.

In one embodiment, a suitable volatile solvent is added to the adhesiveto reduce viscosity and aid solvation. Suitable solvents may include,but are not limited to, isopropyl alcohol, methanol, ethanol and ethylacetate.

Penetration Enhancer

Suitably, the first layer further comprises a penetration enhancer.

The composition may comprise one or more penetration enhancers fortransdermal drug delivery. Examples of penetration enhancers includeC8-C22 fatty acids such as isostearic acid, octanoic acid, myristic acidand oleic acid; C8-C22 fatty alcohols such as oleyl alcohol and laurylalcohol; lower alkyl esters of C8-C22 fatty acids such as ethyl oleate,isopropyl myristate (IPM), butyl stearate, and methyl laurate;di(lower)alkyl esters of C6-C22 diacids such as diisopropyl adipate;monoglycerides of C8-C22 fatty acids such as glyceryl monolaurate;tetrahydrofurfuryl alcohol polyethylene glycol ether; polyethyleneglycol, propylene glycol; 2-(2-ethoxyethoxy) ethanol (transcutol);diethylene glycol monomethyl ether; alkylaryl ethers of polyethyleneoxide; polyethylene oxide monomethyl ethers; polyethylene oxide dimethylethers; dimethyl sulfoxide; glycerol; ethyl acetate; acetoacetic ester;N-alkylpyrrolidone; and terpenes.

In a particular embodiment, the penetration enhancer is oleic acid,myristic acid or 1:1 oleic acid:oleyl alcohol.

In an embodiment, the first layer comprises one penetration enhancer. Inanother embodiment, the composition comprises two penetration enhancers.

The penetration enhancer is present in an amount sufficient to providethe desired physical properties and skin penetration profile for thecomposition.

For example, one or more pharmaceutically acceptable penetrationenhancers can be present in a total amount by weight of 0.1-15% w/w ofthe first layer. In an embodiment, one or more pharmaceuticallyacceptable penetration enhancers are present in a total amount by weightbetween 2% and 12% w/w of the first layer, or between 5% and 12% w/w, orbetween 7% and 11% w/w.

Hydrophilic Materials

In certain embodiments, the use of hydrophilic materials in the firstlayer may aid the skin absorption of the opioid analgesic or thesolubility of the drug in the adhesive. Suitably, the hydrophilicmaterial, and the quantities in which it is added, should be non-toxic,non-irritating, non-allergenic, and compatible with the opioid analgesicand the other excipients herein described.

In one embodiment, the hydrophilic material will have ahydrophilic-lipophilic balance (HLB) of greater than 7. Examples ofhydrophilic materials suitable for inclusion into the pharmaceuticalformulation of the present invention include, but are not limited to,propylene glycol, dipropylene glycol, glycerol, polyethylene glycol,short chain water soluble esters of citric acid, acetic acid, hexyleneglycol and alcohols, including diols and polyols.

The amount of hydrophilic material present is 0-20% w/w.

Suitably, when used, the hydrophilic material is present in the firstlayer in an amount of between 1.0% w/w and 20% w/w.

Suitably, the hydrophilic material, when present, is in an amount ofbetween 0.5 and 10% w/w, and more suitably between 1 and 8% w/w.

Suitably, the hydrophilic material is propylene glycol or dipropyleneglycol.

In an embodiment, the hydrophilic material is included in the firstlayer as part of a mixture including the opioid analgesic, thepharmaceutically acceptable adhesive and a penetration enhancer.

Particular Embodiments of the First Layer

The following represent particular embodiments of the first layer:

1.1 Opioid analgesic (e.g. oxymorphone) 1-10% w/w Pharmaceuticallyacceptable adhesive 58-98% w/w Penetration enhancer (e.g oleic acid,myristic 0.1-15% w/w acid, and/or oleyl alcohol) Hydrophilic material(e.g. propylene glycol) 0-20% w/w 1.2 Opioid analgesic (e.g.oxymorphone) 3-10% w/w Acrylate/polyacrylate adhesive 60-80% w/w (e.g.BIO-PSA 7-4502, 7-4302 and 7-4202) Silicone adhesive (e.g. Duro-Tak9301 ®) 0-15% w/w Penetration enhancer (e.g oleic acid, 2-12% w/wmyristic acid and/or oleyl alcohol) Hydrophilic material (e.g. propyleneglycol) 0-10% w/w 1.3 Opioid analgesic (e.g. oxymorphone) 4-6% w/wAcrylate/polyacrylate adhesive 70-80% w/w (e.g. BIO-PSA 7-4502, 7-4302and 7-4202) Silicone adhesive (e.g. Duro-Tak 9301 ®) 0-12% w/wPenetration enhancer (e.g oleic acid, 5-12% w/w myristic acid, and/oroleyl alcohol) Hydrophilic material (e.g. propylene glycol) 0-8% w/w 1.4Opioid analgesic (e.g. oxymorphone) 4-6% w/w Acrylate/polyacrylateadhesive 70-80% w/w (e.g. BIO-PSA 7-4502, 7-4302 and 7-4202) Siliconeadhesive (e.g. Duro-Tak 9301 ®) 0-12% w/w Penetration enhancer (e.goleic acid, 5-12% w/w myristic acid and/or oleyl alcohol) Hydrophilicmaterial (e.g. propylene glycol) 0-8% w/w

Particular examples of the first layer are provided in Example 1 herein.

The Second Layer

The thickness of the second may be 0.1-100 mil, more suitably 10-75 mil,and even more suitably 15-60 mil.

Opioid Antagonist

Suitably, the opioid antagonist is present in an amount of 1-20% w/w, or8-12% w/w, and even more suitably, 9-11% w/w in the second layer.

The opioid antagonist is suitably selected from the group consisting of:naltrexone (“NTX”), 6-beta-naltrexol, nalbuphine, nalmefene, naloxone(“NLX”), cyclazocine, levallorphan, cyclorphan, oxilorphan andpharmaceutically acceptable salts and prodrugs thereof.

Suitably, the opioid antagonist is naltrexone (“NTX”), naloxone (“NLX”)or nalmefene.

In the first aspect of the present invention, a proportion of the opioidantagonist is present in the form of a pharmaceutically acceptable saltand the remainder is present in a non-salt (e.g. free base) form.

The amount of the salt form of the opioid antagonist present may be5-95% w/w, more suitably 15 to 80% w/w, even more suitably 30-70% w/wand most suitably 45-55% w/w of the total opioid antagonist present inthe second layer (and the balance is the non-salt (e.g. free base)form).

The use of just the non-salt form of the antagonist, e.g. the free baseof naltroxone or naloxone, has been found to result in some migration ofthe antagonist into first layer during use with certain barrier layers.Conversely, the use of just the salt form can prevent this migrationduring use, but then does not give the desired release rate ofantagonist with the opioid when the patch is exposed to solvents such aswater, phosphate buffered saline, ethanol and acetone.

The use of both the salt and non-salt forms together enables a balancebetween the migration through to the first layer during use and theachieving the required release ratio of antagonist to opioid analgesicwhen the patch is subject to abuse. This enables a larger number ofbarrier membranes to be used.

The amount of opioid antagonist present in the second layer of thepatches of the present invention will depend on how soluble it is in thepharmaceutically-acceptable adhesive and any other excipients present inthis layer, and how much of the opioid antagonist is required relativeto the opioid agonist in order to achieve the desired abuse deterrenteffect. Typically, the opioid antagonist will be present at an amount of2-15% w/w in the second layer.

In one embodiment, the opioid antagonist is present in an amount of5-12% w/w in the second layer.

Pharmaceutically-Acceptable Adhesive

The pharmaceutically-acceptable adhesive present in the second layer isselected both in terms of its ability to solubilise the opioidantagonist and its adhesive tack properties.

In one embodiment, the adhesive has an opioid antagonist solubility inexcess of 2.5% w/w at room temperature.

Typically, the amount of adhesive is between 58 and 98% w/w of thesecond layer, and more suitably 60-80% w/w, and even more suitably60-70% w/w.

Any suitable adhesive material or combination of adhesive materials asdefined above in relation to the first layer may be used.

Suitably, an acrylate or polyacrylate adhesive material and/or asilicone adhesive as defiend in relation to the first layer represents50-98% w/w of the second layer, and more suitably 55-75% w/w, and evenmore suitably 60-70% w/w of the second layer.

Additional adhesives, such as, for example, polyvinylpyrollidinone (e.g.polyvinylpyrollidone K30) may also be present, for example in amount ofbetween 0.5 to 15% w/w of the second layer, or 1 to 6% w/w, or 2 to 5%w/w.

In one embodiment, a suitable volatile solvent is added to the adhesiveto reduce viscosity and aid solvation. Suitable solvents may include,but are not limited to, isopropyl alcohol, methanol, ethanol and ethylacetate.

Cellulose Components

The second layer may further comprise 0-30% w/w of cellulose components,for example ethyl cellulose, hydroxypropyl cellulose or a mixturethereof. Suitably, 0-25% w/w of such components may be present.

In an embodiment, the second layer comprises 5 to 25% w/w of cellulosecomponents.

In a further embodiment, the second layer comprises 5 to 25% w/w of anethyl cellulose/hydroxypropyl cellulose mixture (e.g. at a ratio of0.5-10:1 of ethyl cellulose:hydroxypropyl cellulose).

Hydrophilic Materials

The second layer may optionally comprise a hydrophilic material asdefined hereinbefore in relation to the first layer.

The amount of hydrophilic material present in the second layer is 0-20%w/w.

Suitably, when used, the hydrophilic material is present in the secondlayer in an amount of between 1.0% w/w and 10% w/w.

Suitably, the hydrophilic material, when present, is in an amount ofbetween 0.5 and 10% w/w, and more suitably between 1 and 8% w/w.

Suitably, the hydrophilic material is propylene glycol or dipropyleneglycol.

Particular Embodiments of the Second Layer

The following represent particular embodiments of the second layer:

2.1 Opioid antagonist 1-20% w/w Pharmaceutically acceptable adhesive58-98% w/w Cellulose components (e.g ethyl cellulose 0-25% w/w and/orhydroxypropyl cellulose) Hydrophilic material (e.g. propylene glycol0-20% w/w or dipropylene glycol) 2.2 Opioid antagonist 8-12% w/wPharmaceutically acceptable adhesive 60-80% w/w (e.g. BIO-PSA 7-4302and/or Duro-Tak 9301) Cellulose components (e.g ethyl cellulose 0-20%w/w and/or hydroxypropyl cellulose) Hydrophilic material (e.g. propylene0-10% w/w glycol or dipropylene glycol) 2.3 Opioid antagonist 8-12% w/wPharmaceutically acceptable adhesive 60-70% w/w (e.g. BIO-PSA 7-4302and/or Duro-Tak 9301) Cellulose components (e.g ethyl cellulose 0-20%w/w and/or hydroxypropyl cellulose) Hydrophilic material (e.g. propylene0-10% w/w glycol or dipropylene glycol)

Particular examples of the second layer are provided in Example 2herein.

Additional Optional Excipients in the First and Second Layers

In addition to the opioid analgesic, the adhesive and optionally thepenetration enhancer, the first layer may optionally comprise one ormore additional excipients, for example, hydrophilic polymers, wettingagents, emollients, antioxidants or emulsifying agents.

The first and second layers described herein optionally comprise one ormore pharmaceutically acceptable wetting agents as excipients. Examplesof surfactants that can be used as wetting agents in compositions of thedisclosure include quaternary ammonium compounds, for examplebenzalkonium chloride, benzethonium chloride and cetylpyridiniumchloride; dioctyl sodium sulfosuccinate; polyoxyethylene alkylphenylethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9;poloxamers (polyoxyethylene and polyoxypropylene block copolymers);polyoxyethylene fatty acid glycerides and oils, for examplepolyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g.,Labrasol™ of Gattefosse), polyoxyethylene (35) castor oil andpolyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkylethers, for example polyoxyethylene (20) cetostearyl ether;polyoxyethylene fatty acid esters, for example polyoxyethylene (40)stearate; polyoxyethylene sorbitan esters, for example polysorbate 20and polysorbate 80 (e.g., Tween™ 80 of ICI); propylene glycol fatty acidesters, for example propylene glycol laurate (e.g., Lauroglycol™ ofGattefosse); sodium lauryl sulfate, fatty acids and salts thereof, forexample oleic acid, sodium oleate and triethanolamine oleate; glycerylfatty acid esters, for example glyceryl monostearate; sorbitan esters,for example sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate and sorbitan monostearate; tyloxapol; and mixturesthereof. Such wetting agents, if present, constitute in total about0.25% to about 15%, about 0.4% to about 10%, or about 0.5% to about 5%,of the total weight of the composition. Illustratively, one or morepharmaceutically acceptable wetting agents are present in a total amountby weight of about 0.25-10% w/w of the first layer.

The first and second layers described herein optionally comprise one ormore pharmaceutically acceptable lubricants (including anti-adherentsand/or glidants) as excipients. Suitable lubricants include, eitherindividually or in combination, glyceryl behenate (e.g., Compritol™888); stearic acid and salts thereof, including magnesium (magnesiumstearate), calcium and sodium stearates; hydrogenated vegetable oils(e.g., Sterotex™); colloidal silica; talc; waxes; boric acid; sodiumbenzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine;PEG (e.g., Carbowax™ 4000 and Carbowax™ 6000); sodium oleate; sodiumlauryl sulfate; and magnesium lauryl sulfate. Such lubricants, ifpresent, constitute in total about 0.1% to about 10%, about 0.2% toabout 8%, or about 0.25% to about 5%, of the total weight of thecomposition. Illustratively, one or more pharmaceutically acceptablelubricants may be present in a total amount by weight of 0.1% -10.0%.

In another embodiment, the first and second layers described hereinoptionally comprise an emollient. Illustrative emollients includemineral oil, mixtures of mineral oil and lanolin alcohols, cetylalcohol, cetostearyl alcohol, petrolatum, petrolatum and lanolinalcohols, cetyl esters wax, cholesterol, glycerin, glycerylmonostearate, isopropyl myristate (IPM), isopropyl palmitate, lecithin,allyl caproate, althea officinalis extract, arachidyl alcohol, argobaseEUC, butylene glycol, dicaprylate/dicaprate, acacia, allantoin,carrageenan, cetyl dimethicone, cyclomethicone, diethyl succinate,dihydroabietyl behenate, dioctyl adipate, ethyl laurate, ethylpalmitate, ethyl stearate, isoamyl laurate, octanoate, PEG-75, lanolin,sorbitan laurate, walnut oil, wheat germ oil, super refined almond,super refined sesame, super refined soybean, octyl palmitate,caprylic/capric triglyceride and glyceryl cocoate.

An emollient, if present, is present in the first and second layersdescribed herein in an amount of 1% -30% w/w, or 3% -25% w/w, or 5-15%w/w.

In one embodiment, the first and second layers described herein comprisean antioxidant. Illustrative antioxidants include citric acid, butylatedhydroxytoluene (BHT), ascorbic acid, glutathione, retinol,alpha-tocopherol, beta-carotene, alpha-carotene, ubiquinone, butylatedhydroxyanisole, ethylenediaminetetraacetic acid, selenium, zinc, lignan,uric acid, lipoic acid, and N-acetylcysteine. An antioxidant, ifpresent, is present in the first and second layers described herein inthe amount of less than about 1% by weight.

In one embodiment, the first and second layers described herein comprisean antimicrobial preservative. Illustrative anti-microbial preservativesinclude acids, including but not limited to benzoic acid, phenolic acid,sorbic acids, alcohols, benzethonium chloride, bronopol, butylparaben,cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol,ethylparaben, imidurea, methylparaben, phenol, phenoxyethanol,phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate,phenylmercuric nitrate, potassium sorbate, propylparaben, sodiumpropionate, or thimerosal. The anti-microbial preservative, if present,is present in an amount of about 0.1% to 5% w/w, or 0.2% to 3% w/w, or0.3% to 2% w/w.

The first and second layers described herein optionally comprise one ormore emulsifying agents. The term “emulsifying agent” refers to an agentcapable of lowering surface tension between a non-polar and polar phaseand includes compounds defined elsewhere as “self-emulsifying” agents.Suitable emulsifying agents can come from any class of pharmaceuticallyacceptable emulsifying agents including carbohydrates, proteins, highmolecular weight alcohols, wetting agents, waxes and finely dividedsolids. The optional emulsifying agent may be present in the first andsecond layers in a total amount of 1-25% w/w, or 1-20% w/w, or 1-15%w/w, or 1-10% w/w of the first and second layers.

In another embodiment, propylene glycol or dipropylene glycol is presentin a composition in an amount of 1-20% by weight of the first and secondlayers.

The first and second layers described herein may optionally comprise oneor more alcohols. In a further embodiment, the alcohol is a loweralcohol. As used herein, the term “lower alcohol,” alone or incombination, means a straight-chain or branched-chain alcohol moietycontaining one to six carbon atoms. In one embodiment, the lower alcoholcontains one to four carbon atoms, and in another embodiment the loweralcohol contains two or three carbon atoms. Examples of such alcoholmoieties include ethanol, ethanol USP (i.e., 95% v/v), n-propanol,isopropanol, n-butanol, isobutanol, sec-butanol, and tert-butanol. Asused herein, the term “ethanol” refers to C₂H₅OH. It may be used asdehydrated alcohol USP, alcohol USP or in any common form including incombination with various amounts of water. If present, the alcohol ispresent in an amount sufficient to form a composition which is suitablefor contact with a mammal.

In a further embodiment, the pharmaceutical composition is substantiallyfree of water. In yet a further embodiment, the pharmaceuticalcomposition is anhydrous.

Barrier Layer

The barrier layer is disposed between the first and second layers andfunctions to substantially prevent the opioid antagonist diffusing fromthe second layer to the first layer during normal use of the patch. Thebarrier layer also enables the release of the antagonist from the secondlayer at a rate sufficient to inhibit the abuse potential of the opioidanalgesic when the patch is tampered with (by, for example, chewing thepatch or immersing it in a solvent such as water, ethanol or acetone).

As indicated above, the use of a salt and non-salt form of the opioidantagonist enables a larger number of barrier membranes to be used.

In the first aspect of the present invention, any suitable barriermembrane may used. Examples include membranes made from polyethylene,ethylene vinyl acetate, polypropylene (e.g. ultra high densitypolyethylene), polyurethane, polyvinyl acetate, polyvinylidene chloride,polyester, polyethylene terephthalate, polybutylene terephthalate, rayon(synthetic textile fibres produced by forcing cellulose through finespinnerets and solidifying the resultant filaments), wood pulp, andspun-laced polyester.

Preferred membranes include membranes made from polyethylene andethylene vinyl acetate. In particular, Solupor microporous ultra highdensity polyethylene (UHDPE) materials and films (Solupor® manufacturedby DSM Desotech, Denmark) are particularly effective at inhibiting thepermeation of the opioid anatagonist from the second layer to the firstlayer during use (redgardless of whether or not it is in a non-salt orsalt form), yet enabling the antagonist to be released in an abuseinhibiting ratio with the opioid analgesic when the patech is tamperedwith. Ethylene vinyl acetate (EVA) membranes made by 3M under the tradename CoTran are also viable alternatives.

Transdermal Patch of the Second Aspect of the Invention

In a second aspect, the present invention provides a transdermal patchcomprising a multilaminate, said multilaminate comprising:

(i) a first layer comprising an opioid analgesic compound as definedhereinbefore, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable pressure sensitive adhesive;

(ii) a second layer comprising an opioid antagonist, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable adhesive as defined hereinbefore; and

(iii) a barrier layer disposed between the first and second layers, andwherein the barrier layer substantially prevents the opioid antagonistdiffusing from the second layer to the first layer during use;

wherein said barrier layer comprises a material selected from the groupconsisting of polyethylene, ethylene vinyl acetate, polypropylene,polyurethane, polyvinyl acetate, polyvinylidene chloride, polyester,polyethylene terephthalate, polybutylene terephthalate, rayon (synthetictextile fibres produced by forcing cellulose through fine spinnerets andsolidifying the resultant filaments), wood pulp, and spun-lacedpolyester.

The patches of the second aspect of the present invention may be usedwith the antagonist in the second layer either entirely in a non-salt(e.g. free base) or salt form or in a mixture of the free base and saltforms.

Suitably, in the patches of the second aspect of the present invention,the antagonist in the second layer either entirely in a non-salt (e.g.free base) form or in a mixture of the free base and salt forms asdefined above for the first aspect of the invention.

Preferred membranes of the second aspect include membranes made frompolyethylene and ethylene vinyl acetate. In particular, Solupormicroporous ultra high density polyethylene (UHDPE) materials and films(Solupor manufactured by DSM Desotech, Denmark) are particularlyeffective at inhibiting the permeation of the opioid anatagonist fromthe second layer to the first layer during use (redgardless of whetheror not it is in a non-salt or salt form), yet enabling the antagonist tobe released in an abuse inhibiting ratio with the opioid analgesic whenthe patech is tampered with. Ethylene vinyl acetate (EVA) membranes madeby 3M under the trade name CoTran are also viable alternatives.

Combination Patches

In one embodiment, the first layer of the particles defined hereincontaining the opioid can also be combined with an optional secondnon-opioid pharmacologically active agent for the treatment of painand/or polydrug abuse, including, for example, a cannabinoid (agonist,antagonist, or inverse agonist), bupropion, hydroxybupropion, nicotine,nornicotine, varenicline, doxepin, acetaminophen, aspirin, diclofenac oranother non-steroidal anti-inflammatory drug.

Therapeutic Uses

The patches of the present invention may be used for the treatment ofone or more medical conditions, such as opioid dependence, alcoholdependence, polydrug addiction, pain, cocaine addiction, eatingdisorders (e.g., binge eating) and treatment-resistant depression aredescribed herein and comprise transdermally administering an opioid froman formulation as defined herein. In one embodiment, compositionsdescribed herein which are transdermally administrable include opioidanalgesics such as oxymorphone and opioid antagonists, such asnaltrexone and/or naloxone.

The compositions described herein are used in a “pharmacologicallyeffective amount.” This means that the rate and extent of absorption ofthe active by the subject is such that it results in a therapeutic levelof the active in the subject over the period that such compound is to beused. Such delivery is dependent on a number of variables including thetime period for which the individual dosage unit is to be used, the fluxrate of the active from the composition into the subject, for example,buprenorphine or a buprenorphine prodrug, from the formulation, surfacearea of the application site, etc.

In another embodiment, a single dosage unit comprises a therapeuticallyeffective amount or a therapeutically and/or prophylactically effectiveamount of an opioid analgesic such as oxymorphone. The term“therapeutically effective amount” or “therapeutically and/orprophylactically effective amount” as used herein refers to an amount ofopioid that is sufficient to elicit the required or desired therapeuticand/or prophylactic response, as the particular treatment context mayrequire. Single dosage unit as used herein includes individual patches.In one embodiment, a single dosage unit of any formulation comprises atherapeutically effective amount or a therapeutically and/orprophylactically effective amount of buprenorphine or a buprenorphineprodrug.

It will be understood that a therapeutically and/or prophylacticallyeffective amount of an opioid for a subject is dependent inter alia onthe body weight of the subject as well as other factors known to aperson of ordinary skill in the art. A “subject” herein to which atherapeutic agent or composition thereof can be administered includesmammals such as a human of either sex and of any age, and also includesany nonhuman animal, particularly a domestic, farm or companion animal,illustratively, a cat, cow, pig, dog or a horse as well as laboratoryanimals such as guinea pigs and primates.

In one embodiment, compositions described herein are suitable fortransdermal administration. In another embodiment, transdermallyadministrable compositions are adapted for administration to theabdomen, back, chest, legs, arms, scalp or other suitable skin surface.

The terms “treat”, “treated”, “treating” and “treatment” are to bebroadly understood as referring to any response to, or anticipation of,a medical condition in a mammal, particularly a human, and includes butis not limited to: (i) inhibiting the medical condition, i.e.,arresting, slowing or delaying the on-set, development or progression ofthe medical condition; or (ii) relieving the medical condition, i.e.,causing regression of the medical condition.

In one embodiment, a therapeutically effective amount of an opioid, suchas buprenorphine, is administered transdermally in an formulation asdefined herein to treat a medical condition selected from the groupconsisting of: opioid dependence, alcohol dependence, polydrugaddiction, pain, cocaine addiction, eating disorders (e.g., bingeeating) and treatment-resistant depression.

Pain can include nociceptive pain, such as somatic pain and visceralpain, and non-nociceptive pain, such as neuropathic pain, sympatheticpain, psychogenic pain and idiopathic pain. Pain also includes chronicand acute pain. Non-limiting examples of pain or sources of pain includefibromyalgia, chronic back pain (both deep and superficial somaticpain), chronic pancreatitis, chronic acute hepatitis, gallstone,appendicitis, post-herpetic neuralgia, trigeminal neuralgia, phantomlimb pain, diabetic neuropathy, carpal tunnel syndrome, sciatica,pudendal neuralgia, central pain syndrome, spinal cord injury,post-surgical pain, cancer, degenerative disk disease, osteoporosis,peripheral neuropathy, herpes zoster (shingles), lupus, reflexsympathetic dystrophy, headaches (migraines, tension and cluster),temporomandibular disorders, such as temporomandibular joint syndrome,myofacial pain and internal derangement of the joint and degenerativejoint disease, such as osteoarthritis and rheumatoid arthritis.

Eating disorders can include anorexia nervosa, bulimia nervosa, bingeeating disorder (BED), compulsive overeating, purging disorder,rumination, diabulimia, food maintenance, eating disorders not otherwisespecified (EDNOS), pica, night eating syndrome and orthorexia nervosa.

In one embodiment, the pharmaceutical composition comprising an opioid,such as oxymorphone, is administered once daily to a subject in needthereof. In a further embodiment, the pharmaceutical compositioncomprising an opioid, such as oxymorphone, is administered twice dailyto a subject in need thereof.

In another illustrative embodiment, a transdermal patch can be one whichis capable of controlling the release of the opioid agonists oragonist-antagonists or prodrugs of the foregoing such that transdermaldelivery of the active compound is substantially uniform and sustainedover a period of about 6 hours, about 12 hours, about 24 hours, about 48hours or about 7 days. Such transdermal patch which can be used in thepractice of the methods described herein can take the form of anocclusive body having a backing layer. In practice, the occlusive bodywhich includes the opioid agonists or agonist-antagonists or prodrugs ofthe foregoing is positioned on the subject's skin under conditionssuitable for transdermally delivering the active compound to the subject

Preparation of Pharmaceutical Formulations

The transdermal patches of the present invention can be prepared usingconventional techniques known in the art.

Transdermal Patches Comprising the First Layer Only

The first layer defined herein is suitably prepared by mixing all of thecomponents together. The individual components may be mixed by simplyadding all of the components at the same time into a mixing vessel andthen mixing them all together (a “one-pot” mixture). Alternatively, thecomponents may be added sequentially in two or more steps or stages.

Other experimental conditions required to prepare the formulations ofthe present invention, such as mixing times, mixing equipment,temperature control etc. can be readily determined by a person ofordinary skill in the art.

Further experimental details will also be evident from the accompanyingExamples.

Once components have been mixed together the layers can be prepared bywet casting a desired thickness onto a suitable surface, e.g. a releaseliner. The layer can then be dried and stored ready for assembly.

Typically, the first layer is cast at a wet thickness of between about240 μm to about 550 μm, to provide a dry thickness of between about 45μm and about 95 μm, suitably between about 80 μm and about 85 μm. Aftercasting, the layers are dried.

Suitably, the first layer is wet cast onto a release liner as definedherein (e.g. 3M Scotchpak 1022).

Transdermal Patches Comprising the First, Second and Barrier layer

The first and second layers defined herein are suitably prepared bymixing all of the components together. The individual components may bemixed by simply adding all of the components at the same time into amixing vessel and then mixing them all together (a “one-pot” mixture).Alternatively, the components may be added sequentially in two or moresteps or stages.

Other experimental conditions required to prepare the formulations ofthe present invention, such as mixing times, mixing equipment,temperature control etc. can be readily determined by a person ofordinary skill in the art.

Further experimental details will also be evident from the accompanyingExamples.

Once components have been mixed together the layers can be prepared bywet casting a desired thickness onto a suitable surface, e.g. a releaseliner. The layer can then be dried and stored ready for assembly.

Typically, the first and second layers are cast at a wet thickness ofbetween about 240 μm to about 550 μm, to provide a dry thickness ofbetween about 45 μm and about 95 μm, suitably between about 80 μm andabout 85 μm. After casting, the layers are dried.

The layers are assembled to form the multilaminate structures definedherein. Suitably, the first layer is wet cast onto a release liner asdefined herein (e.g. 3M Scotchpak 1022). One surface of the first layeris therefore in contact with the release liner and the barrier membraneis applied to the opposing surface, followed by the second layer and abacking membrane to complete the assembly of the patch.

EXAMPLES

Examples of the invention will now be described, for the purpose ofreference and illustration only, with reference to the accompanyingfigures, in which:

FIG. 1 shows the representative human skin permeation profile ofoxymorphone formulation, OM-2014-01-011 (n=3);

FIG. 2 shows the representative cumulative human skin permeation profileof oxymorphone formulation, OM-2014-01-011 (n=3);

FIG. 3 shows the representative time interval flux values of oxymorphoneformulation, OM-2014-01-011 (n=3);

FIG. 4 shows the representative human skin permeation profile ofoxymorphone formulations, OM-2014-01-012 (n=4) & OM-2014-01-013 (n=4);

FIG. 5 shows the representative cumulative human skin permeation profileof oxymorphone formulations, OM-2014-01-012 (n=4) & OM-2014-01-13 (n=4);

FIG. 6 shows the representative time interval flux values of oxymorphoneformulation, OM-2014-01-012 (n=4) and OM-2014-01-013 (n=4);

FIG. 7 shows the representative human skin permeation profile ofoxymorphone formulations, OM-2014-01-014 (n=4), OM-2014-01-015 (n=4) &OM-2014-01-019 (n=4);

FIG. 8 shows the representative cumulative human skin permeation profileof oxymorphone formulations, OM-2014-01-014 (n=4), OM-2014-01-015 (n=4)& OM-2014-01-019 (n=4);

FIG. 9 shows the representative time interval flux values of oxymorphoneformulation, OM-2014-01-014 (n=4), OM-2014-01-015 (n=4), andOM-2014-01-019 (n=4);

FIG. 10 shows the representative human skin permeation profile ofoxymorphone formulation, OM-2014-01-014 (n=4), different skin donor(repeat study);

FIG. 11 shows the representative cumulative human skin permeationprofile of oxymorphone formulation, OM-2014-01-014 (n=4), different skindonor (repeat study);

FIG. 12 shows the representative time interval flux values ofoxymorphone formulation, OM-2014-01-014 (n=4), different skin donor(repeat study);

FIG. 13 shows the representative human skin permeation profile ofoxymorphone formulations, OM-2014-01-020 (n=3), OM-2014-01-021 (n=3),OM-2014-01-022 (n=3) & OM-2014-01-023 (n=3);

FIG. 14 shows the representative cumulative human skin permeationprofile of oxymorphone formulations, OM-2014-01-020 (n=3),OM-2014-01-021 (n=3), OM-2014-01-022 (n=3) & OM-2014-01-023 (n=3);

FIG. 15 shows the representative point flux estimations of oxymorphoneformulations, OM-2014-01-020 (n=3), OM-2014-01-021 (n=3), OM-2014-01-022(n=3) & OM-2014-01-023 (n=3);

FIG. 16 shows the representative human skin permeation profile ofoxymorphone formulation, OM-2014-01-043 (n=4).

FIG. 17 shows the representative human skin permeation profile ofoxymorphone formulation, OM-2014-01-046 (n=4) (pig skin).

FIG. 18 shows the representative human skin permeation profile ofoxymorphone formulation, OM-2014-01-046 (n=4) for skin donor one (whitefemale, aged 65).

FIG. 19 shows the representative human skin permeation profile ofoxymorphone formulations, OM-2014-01-046 (n=4) for skin donor two (blackfemale, aged 46).

FIG. 20 shows the representative human skin permeation profile ofoxymorphone formulations, OM-2014-01-046 (n=4) for skin donor three(white female, aged 59).

FIG. 21 shows the representative human skin permeation profile ofoxymorphone formulations, OM-2014-01-047 (n=4).

FIG. 22 shows the representative human skin permeation profile ofoxymorphone formulations, OM-2014-01-048 (n=4).

FIG. 23 shows an exemplary abuse-deterrent transdermal patch assemblyprotocol.

FIG. 24 shows an exemplary assembled abuse-deterrent transdermal patch(not to scale).

Materials and Procedures Chemicals

The various chemicals used throughout these examples are as follows:

Chemical Manufacturer Part # CAS Lot # Oxymorphone Mallinckrodt Inc.079006 357-07-3 1304000913 hydrochloride, USP Potassium phosphate,Fisher Scientific BP362-500 7778-77-0 132450 monobasic Potassiumphosphate Acros Organics AC20593- 16788-57-1 A0331382 dibasic trihydrate5000 Propylene glycol, USP Spectrum Chemicals PR130-500mL 57-55-62BG0259 Ethanol, 200 proof, Sigma Aldrich 493546- 64-17-5 SHB04820V USP500mL Alcohol (ethyl alcohol) Spectrum ET108 64-17-5, 7732-18-5 2CD0092190 proof USP Ethyl acetate, NF Fisher Scientific E124-20 141-78-6134168 Myristic acid myristyl MP Biomedicals 0215575591 3234-85-3 155755ester Oleic acid, NF Spectrum Chemicals OL103-1LTGL 112-80-1 Myristicacid, reagent Spectrum Chemicals MY110- 544-63-8 WV3017 100GM BIO-PSAAC7-4302 Dow Corning 3275205 238094-36-5, 141-78- 0006099302 6,1330-20-7 BIO-PSA 7-4202 Dow Corning 000015563317 238094-36-5, 141-78-0006001327 6, 1330-20-7 Duro-Tak ® 2054 Henkel 387-2054 200-661-7,205-500-4, 2Q939447717 203-624-3, 203-625-9 237-741-6, 203-806-2,205-480-7 Duro-Tak ® 608A Henkel 1214080 142-82-5, 9003-27-4 20382-12Duro-Tak ® 4098 Henkel 1219326 141-78-6, 108-05-4 OH31424641 Duro-Tak ®9301 Henkel 1428620 141-78-6 OH14495473 Duro-Tak ® 202A Henkel 87-202A141-78-6, 67-63-0, 67- OH90213550 56-1 Klucel ® EF PH HerculesIncorporated NA 9004-64-2 99860 Aqualon ® EC-N50 PH HerculesIncorporated NA 9004-57-3 42118 Polyvinylpyrollidone Spectrum ChemicalsP1454 9003-39-8 XQ0602 (PVP-K30) Polyvinylpyrollidone Sigma Aldrich190845-250g 25086-89-9 MKBC1985 vinyl acetate Chloroform JT Baker9182-01 67-66-3 J02B18 Sodium hydroxide JT Baker 3722-01 1310-73-2J20K52 Sodium chloride Fisher Scientific M-11624 7647-14-5 102040Acetonitrile, HPLC Fisher Scientific A998-4 75-05-8 138059 gradeMethanol, HPLC grade Fisher Scientific A452-4 67-56-1 124875

Supplies

Supplies used throughout these examples are as follows:

1) XBridge® C18 column; 5 μm, 4.6×250 mm, Waters Corporation, partnumber 186003117, serial number 01513230622) Clear target DPTM HPLC vials with pre-slit tef/white silicone septacaps; 100/pk, National Scientific, part number C4000-95P3) Scintillation vials and caps; 20 mL low background borosilicate glassvial, polypropylene cap with metal foil liner; Research ProductsInternational Corp., part number 121000W04) Nylon membrane filter; Millipore, 0.2 μm GNWP, part number GNWP04700

Equipment

The equipment used throughout these examples is as follows:

1) INST-004 2695 Alliance separations module, Waters Corporation2) INST-005 2487 Dual wavelength absorbance detector, Waters Corporation3) INST-006 Column heater, Waters Corporation4) INST-021 Retriever IV fraction collector, Isco5) INST-025 Retriever IV fraction collector, Isco6) INST-033 Retriever IV fraction collector, Isco7) INST-023 Heated water bath, Thermo8) INST-027 Heated water bath, Thermo9) INST-031 Heated water bath, Thermo10) INST-026 Heated circulating water bath, Fisher Scientific11) INST-030 Heated circulating water bath, VWR International12) INST-028 16 channel pump, Watson Marlow13) INST-032 16 channel pump, Watson Marlow14) INST-034 16 channel pump, Watson Marlow15) INST-064 Model S slimline dermatome, Integra Life Sciences

16) INST-072 Balance, Sartorius 17) INST-078 Pump, KNF Laboport

18) INST-083 Caliper spring micrometer, Mitutoyo Corporation19) INST-088 Dlamond™ UV/UF NANOpure® system, Barnstead International20) INST-116 AB15 pH meter, Fisher Scientific

Opioid Preparation

Oxymorphone base was obtained from commercial oxymorphone hydrochlorideby reacting an aqueous solution of the oxymorphone hydrochloride with anaqueous solution of sodium hydroxide. The resulting precipitate wasfiltered off, washed twice with water and dried overnight under highvacuum.

Receiver Fluids

Isotonic phosphate buffer pH 6.3 was prepared by combining 1600 mL of a0.067 M potassium phosphate, monobasic solution to 400 mL of a 0.13 Mpotassium phosphate, dibasic trihydrate solution. 4.4 g/L sodiumchloride was then added to the buffer. The resulting mixture had ameasured pH of 6.3. The water was obtained from a NANOpure® Dlamond™Life Science (UV/UF) ultrapure water system. The phosphate buffer wasfiltered (0.2 pm nylon membrane filter) and placed in a 2 L glassbottle.

A 10% ethanol in water receiver solution was prepared by adding 210 mLof ethyl acohol (190 Proof) to 1790 mL NANOpure® water. The receiversolution was then filtered (0.2 μm nylon membrane filter) and placed ina 2 L glass bottle.

Skin Preparation

Full thickness abdominal tissue with attached fat, harvested fromabdominoplasty, was received. Skin was dermatomed (Model S slimlinedermatome) to a thickness of ˜250 μm. Dermatomed skin was stored at −20°C. until used for the permeation studies.

Permeation Studies

A PermeGear flow-through (In-Line, Hellertown, Pa.) diffusion cellsystem with supports was used for the skin permeation studies. Thefollowing protocol was used:

Diffusion cells were kept at 32° C. with a heated circulating waterbath. The transdermal drug delivery system circular disc was placed onthe skin and pressed down to ensure secure contact with the skin. Humanskin was arranged in the diffusion cell with epidermis (upper layer ofskin) facing the donor compartment. Each cell was charged with acircular disc cut (0.95 cm²) from the respective transdermal drugdelivery system. Permeation area of the skin was 0.95 cm². Diffusioncells remained uncovered to mimic clinical conditions for the durationof the study. Data was collected from a single human skin donor with 3-4diffusion cells per formulation.

Receiver solution was initially a pH 6.3 isotonic phosphate buffer butwas later switched to 10% aqueous ethanol. The flow rate was set to ˜1.1mUh in order to help maintain sink conditions.

Samples were collected into scintillation vials at 8, 16, 24, 32, 40,48, 56, 64 and 72 hour time points.

At the end of the 72 hour experiment, the skin concentrations weredetermined and patches were extracted.

The diffusion samples were analysed the day of collection or thefollowing day.

Dose Administration

A 0.95 cm² circular disc from the respective transdermal drug deliverysystem was cut to fit the In-line diffusional area. The 0.95 cm²transdermal drug delivery system circular disc was placed on the skinand pressed down to ensure secure contact with the skin. Once cells wereequilibrated, the study was initiated by starting the fraction collectorand collecting fractions for the respective time increments.

Analytical Methods

Quantification of oxymorphone was done by high performance liquidchromatography (HPLC). Briefly, HPLC was conducted on a Waters 2695Alliance separations module and column heater with a 2487 dualwavelength absorbance detector. The solvent system consisting of 35% A)acetonitrile and 65% B) phosphate buffer, pH 8.0 was run through aWaters XBridge® C₁₈ 5 μm, 4.6×250 mm column at a flow rate of 1.0mL/min. 50 μL of the diffusion samples and 20 μL for the skin sampleswere injected onto the HPLC column. The limit of detection was 0.043μg/mL. Samples were analysed the day of collection or the following day.

Example 1 Opioid Layer Typical Preparation of Oxymorphone Formulations

The following series of steps provide a typical protocol for thepreparation of the oxymorphone formulations forming part of theinvention (in this specific example, the preparation of a 5% oxymorphonematrix layer (1 kg)). Materials and amounts may vary depending onspecific composition of formulations.

1. Weigh 50 g oxymorphone base into a mixing vessel (5% w/w).

2. Tare weight and add 100 g of oleic acid, NF to the vessel (10% w/w).

3. Pipet 60 mL of ethanol (200 proof) into the vessel.

4. Pipet 260 mL of ethyl acetate into the vessel.

5. Begin mixing and blend until and oxymorphone is completely dissolved.

6. Add 242.1 g Duro-Tak® 9301 (non-volatile content (NVC=41.3%) (10%w/w).

7. Add 1219.5 kg Dow® BIO-PSA 7-4302 (non-volatile content (NVC=61.5%)(75% w/w).

8. Blend until a homogenous viscous solution is achieved.

9. Extrude at 20 mil wet thickness onto 3M™ Scotchpak™ 1022 releaseliner and air dry for 15 minutes at 25° C.

10. Oven dry at 90° C. for 15 minutes.

11. Laminate with 3M™ Scotchpak™ 1022 release liner and reroll for thecomplete patch assembly.

12. Store desiccated until ready for use.

Oxymorphone Formulations

The composition of exemplary oxymorphone formulations are summarizedbelow. Formulations were prepared on a 1 gram scale. Addition ofsolvent, ethanol and ethyl acetate were added to enhance solubility andmixing of solid excipients.

OM-2014-01-001 3% Oxymorphone 97% Dow Corning ® BIO-PSA 7-4502 100 μLEthanol OM-2014-01-002 3% Oxymorphone 97% Dow Corning ® BIO-PSA 7-4302(amine compatible) 100 μL Ethanol OM-2014-01-003 8% Oxymorphone 92%Duro-Tak ® 2054 Acrylic (—COOH functional group) 100 μL EthanolOM-2014-01-004 3% Oxymorphone 97% Duro-Tak ® 4098 Acrylic(non-functional group) 100 μL Ethanol OM-2014-01-005 3% Oxymorphone 97%Duro-Tak ® 608A Polyisobutylene [PIB] 100 μL Ethanol OM-2014-01-006 6%Oxymorphone 94% Duro-Tak ® 202A Acrylic (—OH functional group) 100 μLEthanol OM-2014-01-007 5% Oxymorphone 95% Dow Corning ® BIO-PSA7-4302/Duro-Tak ® 2054 Acrylic (80:20) 150 μL Ethanol OM-2014-01-008 5%Oxymorphone 89% Dow Corning ® BIO-PSA 7-4302/Duro-Tak ® 2054 Acrylic(80:20) 6% Lactic acid 150 μL Ethanol OM-2014-01-009 5% Oxymorphone 5%Polyvinylpyrollidone [PVP-K30] (MW 30,000) 5% Polyvinylpyrollidone vinylacetate [PVP-VA] 7.5% Myristic acid 70.5% Dow Corning ® BIO-PSA7-4302:BIO-PSA 7- 4202 (75:25) 7% Duro-Tak ® 9301 60 μL Ethanol 260 μLEthyl acetate OM-2014-01-010 5% Oxymorphone 5% Polyvinylpyrollidone[PVP-K30] (MW 30,000) 5% Polyvinylpyrollidone vinyl acetate [PVP-VA] 5%Myristic acid 7.5% Myristyl myristate 65.5% Dow Corning ® BIO-PSA7-4302:BIO-PSA 7- 4202 (75:25) 7% Duro-Tak ® 9301 60 μL Ethanol 260 μLEthyl acetate OM-2014-01-011 5% Oxymorphone 2.5% Polyvinylpyrollidone[PVP-K30] (MW 30,000) 2.5% Polyvinylpyrollidone vinyl acetate [PVP-VA]7.5% Oleic acid 10% Propylene glycol 65.5% Dow Corning ® BIO-PSA7-4302:BIO-PSA 7- 4202 (75:25) 7% Duro-Tak ® 9301 60 μL Ethanol 260 μLEthyl acetate OM-2014-01-012 5% Oxymorphone 2.5% Polyvinylpyrollidone[PVP-K30] (MW 30,000) 2.5% Polyvinylpyrollidone vinyl acetate [PVP-VA]7.5% Oleic acid 5% Propylene glycol 70.5% Dow Corning ® BIO-PSA7-4302:BIO-PSA 7- 4202 (75:25) 7% Duro-Tak ® 9301 60 μL Ethanol 260 μLEthyl acetate OM-2014-01-013 5% Oxymorphone 2.5% Polyvinylpyrollidone[PVP-K30] (MW 30,000) 2.5% Polyvinylpyrollidone vinyl acetate [PVP-VA]7.5% Myristic acid 5% Propylene glycol 70.5% Dow Corning ® BIO-PSA7-4302:BIO-PSA 7- 4202 (75:25) 7% Duro-Tak ® 9301 60 μL Ethanol 260 μLEthyl acetate OM-2014-01-014 5% Oxymorphone 7.5% Oleic acid 87.5% DowCorning ® BIO-PSA 7-4302 60 μL Ethanol 260 μL Ethyl acetateOM-2014-01-015 5% Oxymorphone 5% Polyvinylpyrollidone [PVP-K30] (MW30,000) 7.5% Oleic acid 82.5% Dow Corning ® BIO-PSA 7-4302 60 μL Ethanol260 μL Ethyl acetate OM-2014-01-016 5% Oxymorphone 5%Polyvinylpyrollidone [PVP-K30] (MW 30,000) 7.5% Oleic acid 7.5%Propylene glycol 75% Dow Corning ® BIO-PSA 7-4302 60 μL Ethanol 200 μLEthyl acetate OM-2014-01-017 5% Oxymorphone 5% Polyvinylpyrollidonevinyl acetate [PVP-VA] 7.5% Oleic acid 7.5% Propylene glycol 75% DowCorning ® BIO-PSA 7-4302 60 μL Ethanol 200 μL Ethyl acetateOM-2014-01-018 5% Oxymorphone 2.5% Polyvinylpyrollidone [PVP-K30] (MW30,000) 2.5% Polyvinylpyrollidone vinyl acetate [PVP-VA] 5% Oleic acid7.5% Propylene glycol 77.5% Dow Corning ® BIO-PSA 7-4302 60 μL Ethanol200 μL Ethyl acetate OM-2014-01-019 5% Oxymorphone 2.5%Polyvinylpyrollidone [PVP-K30] (MW 30,000) 2.5% Polyvinylpyrollidonevinyl acetate [PVP-VA] 5% Oleic acid 7.5% Propylene glycol 67.5% DowCorning ® BIO-PSA 7-4302:BIO-PSA 7- 4202 (75:25) 10% Duro-Tak ® 9301 60μL Ethanol 200 μL Ethyl acetate OM-2014-01-020 5% Oxymorphone 7.5% Oleicacid 87.5% Dow Corning ® BIO-PSA 7-4302 50 μL Ethanol 150 μL Ethylacetate OM-2014-01-021 5% Oxymorphone 7.5% Oleic acid 2.5% Propyleneglycol 75% Dow Corning ® BIO-PSA 7-4302 10% Duro-Tak ® 9301 50 μLEthanol 150 μL Ethyl acetate OM-2014-01-022 5% Oxymorphone 7.5% Oleicacid 77.5% Dow Corning ® BIO-PSA 7-4302 10% Duro-Tak ® 9301 60 μLEthanol 200 μL Ethyl acetate OM-2014-01-023 5% Oxymorphone 7.5% Oleicacid 2.5% Propylene glycol 77.5% Dow Corning ® BIO-PSA 7-4302 10%Duro-Tak ® 9301 60 μL Ethanol 200 μL Ethyl acetate OM-2014-01-024 3.5%oxymorphone 7.5% oleic acid 77.5% Dow Corning BIO-PSA 7-4302 11.5%Duro-tak 9301 60 ul Ethanol 200 ul ethyl acetate OM-2014-01-025 5%oxymorphone 8.5% myristic acid 76.5% Dow Corning BIO-PSA 7-4302 10%Duro-tak 9301 60 ul Ethanol 200 ul ethyl acetate OM-2014-01-028 5%Oxymorphone 10% oleic acid 75% Dow Corning BIO-PSA 7-4302 10% Duro-tak9301 60 ul Ethanol 260 ul ethyl acetate OM-2014-01-030 5% Oxymorphone10% oleic acid 75% Dow Corning BIO-PSA 7-4302 10% Duro-tak 9301 155 ulEthanol 155 ul ethyl acetate OM-2014-01-043 5% oxymorphone 7.5% oleylalcohol 5% PVP K30 82.5% Duro-Tak 4098 400 ul ethanol 100 ul EtOAcOM-2014-01-046 5% Oxymorphone 10% (1:1 oleic acid:oleyl alcohol) 5%PVP-K30 80% Duro-tak 4098 OM-2014-01-047 5% Oxymorphone 10% (1:1 ethyloleate:oleyl alcohol) 5% PVP-K30 80% Duro-tak 4098 OM-2014-01-048 5%Oxymorphone 10% (1:1 oleyl oleate:oleyl alcohol) 5% PVP-K30 80% Duro-tak4098

Oxymorphone Formulation Test Data

FIG. 1 and Table 1 below provide permeation data of oxymorphoneformulation OM-2014-01-011 (n=3) with pH 6.3 isotonic phosphate bufferreceiver solution.

TABLE 1 Permeation data of oxymorphone formulation OM-2014-01-011 (n =3) with pH 6.3 isotonic phosphate buffer receiver solution* 72 h skin 72h concentration cumulative amount Flux Compound (μmol/g) (μg) (μg/cm²/h)OM-2014-01-011 2.2 ± 0.2 544.3 ± 113.8 7.6 ± 2.0 *One cell was removedfrom data set (outlier)

FIG. 2 shows representative cumulative human skin permeation profile ofoxymorphone formulation, OM-2014-01-011 (n=3). FIG. 3 showsrepresentative time interval flux values of oxymorphone formulation,OM-2014-01-011 (n=3).

Formulations OM-2014-01-012 and OM-2014-01-013 focused on decreasingpropylene glycol (PG) content by 5% in both formulations while holdingconstant the PVP-K30, PVP-VA, and acid concentration. Reduction of PG to5% decreased permeation as compared to formulation OM-2014-01-011. Thisreduction in PG content may have influenced the permeability ofoxymorphone out of the matrix by creating a more non porous pathway dueto an overall increase in solid content. Results are shown in Table 2and FIGS. 4, 5, and 6 for OM-2014-01-012 and OM-2014-01-013.

TABLE 2 Permeation data of oxymorphone formulation OM-2014-01- 012 (n =4) & OM-2014-01-013 (n = 4) with 10% aqueous ethanol receiver solution72 h skin 72 h concentration cumulative amount Flux Compound (μmol/g)(μg) (μg/cm²/h) OM-2014-01-012 ND 88.0 ± 18.9 1.2 ± 0.3 OM-2014-01-013ND 95.2 ± 39.4 1.3 ± 0.7 ND = none determined

Despite being viable opioid formulations, formulations OM-2014-01-016,OM-2014-01-017, and OM-2014-01-018 were not tested for inclusion in atransdermal patch due to non-uniform matrix formulation when cast ontothe release liner and dried. Formulations OM-2014-01-014 andOM-2014-01-015 were more white in appearance than other formulationswhen mixed and uniform casts prepared; however upon observation afterdrying, no solid particulates were observed. The addition of Duro-Tak®9301 to formulation OM-2014-01-019 provided enhanced solubility uponmixing; therefore a more transparent film was observed upon casting anddrying. Results are shown in Table 3 and FIGS. 7, 8, and 9 forOM-2014-01-014, OM-2014-01-015, and OM-2014-01-019.

TABLE 3 Permeation data of oxymorphone formulation OM-2014-01- 014 (n =4), OM-2014-01-015 (n = 4), & OM-2014- 01-019 (n = 4) with 10% aqueousethanol receiver solution 72 h skin 72 h concentration cumulative amountFlux Compound (μmol/g) (μg) (μg/cm²/h) OM-2014-01-014 22.7 ± 8.8 263.5 ±82.8 3.7 ± 1.3 OM-2014-01-015  7.5 ± 1.1 147.4 ± 19.8 2.1 ± 0.4OM-2014-01-019 14.2 ± 5.0 355.2 ± 47.2 4.9 ± 0.8

Based on initial positive results, formulation OM-2014-01-014 wasrepeated on a different skin donor to confirm the flux value. Eventhough OM-2014-01-019 had a higher flux value compared toOM-2014-01-014, OM-2014-01-019 was not repeated due to the relativecomplexity of the formulation. Results are shown in Table 4 and FIGS.10, 11, and 12 for OM-2014-01-014.

TABLE 4 Permeation data of oxymorphone formulation OM-2014-01-014 (n =4), on a different skin donor for flux confirmation with 10% aqueousethanol receiver solution (repeat study) 72 h skin 72 h concentrationcumulative amount Flux Compound (μmol/g) (μg) (μg/cm²/h) OM-2014-01-01418.2 ± 4.8 307.0 ± 42.5 4.3 ± 1.0

Formulations OM-2014-01-020, OM-2014-01-021, OM-2014-01-022, andOM-2014-01-023 were prepared in order to investigate small differencesin amounts of additional ethanol and ethyl acetate as well as theaddition of PG and Duro-Tak® 9301 into the formulation. Initially,formulations OM-2014-01-020 and OM-2014-01-021 were to be prepared withno addition of ethanol or ethyl acetate; however, mixing was difficultand a minimal amount was added. Both formulations were cast at 15 milwet thickness compared to 20 mil wet thickness of all previousformulations and formulations, OM-2014-01-022 and OM-2014-01-023.Formulation OM-2014-01-022 showed the best results, with an average fluxof 3.1±1.0 pg/cm²/h. This formulation containing 10% Duro-Tak® 9301 willprovide better wear during therapy and was therefore selected forfurther studied along with OM-2014-01-014 for flux and with the abusedeterrent platform. Results are shown in Table 5 and FIGS. 13, 14, and15 for OM-2014-01-020, OM-2014-01-021, OM-2014-01-022, andOM-2014-01-23.

TABLE 5 Permeation data of oxymorphone formulation OM-2014- 01-020 (n =3), OM-2014-01-021 (n = 3), OM-2014-01-022 (n = 3) & OM-2014-01-023 (n =3) with 10% aqueous ethanol receiver solution 72 h skin 72 hconcentration cumulative amount Flux Compound (μmol/g) (μg/cm²)(μg/cm²/h) OM-2014-01-020 12.4 ± 1.9   83.0 ± 12.6 1.2 ± 0.3OM-2014-01-021 9.7 ± 4.9 83.0 ± 9.7 1.2 ± 0.2 OM-2014-01-022 10.1 ± 13.2225.6 ± 71.5 3.1 ± 1.0 OM-2014-01-023 2.6 ± 1.3 135.0 ± 40.9 1.9 ± 0.6

A variety of adhesive systems, enhancers and cosolvents were employed toobserve permeation differences within these systems. In general,solubility in acrylic adhesives (i.e. Duro-Tak®) was higher, and thusthe driving force out of the patch would be relatively lower. Solubilityin silicone adhesives was lower and thus provided a much higher drivingconstant out of the formulation and into the skin; however, due to therelatively lower solubility, a solubility enhancer that also assisted insolubilising the skin was utilized. Three acids (lactic acid (MW: 90.08,myristic acid (MW: 228.38) and oleic acid (MW: 282.47)) were screenedfor permeation and solubility enhancement. Oleic acid, the mosthydrophobic acid screened, almost immediately dissolved 5% w/w OXYduring formulation preparation and provided enhancement to obtain thedesired permeation rate. Oleic acid is currently approved in 6 topicaland transdermal formulations according to the FDA's inactive ingredientlist. Owing to their fewer number of additives that may have a negativeeffect of cohesive properties, an opiate containing layer such asOM-2014-01-014 or OM-2014-01-022 provides preferred wear characteristicsas well as delivery rates.

For oxymorphone, the required therapeutic flux value is 3.97 μg/cm²/hfor a 42 cm² transdermal drug delivery system (see Table 6 below).Currently with formulation OM-2014-01-014, the flux value is 4.0±1.2μg/cm²/h (n=8). The cumulative permeation of oxymorphone is 285.3±65.2μg/cm² (n=8). Based on these results, a 42 cm² transdermal drug deliverysystem would delivery at the therapeutic levels for 3 days. Theestimated drug load per patch would be 38.2 mg for a 42 cm² patch.

The apparent lag time for all formulations ranged from 16-24 h based onpoint flux estimation calculations. That is, lag time was estimated fromthe point at which flux over time became statistically constant.

Time increments of 8 h for 72 h duration were chosen for initialscreening. Time increments as described in the proposal will be used forcompleting the in vitro permeation studies with the optimizedformulation(s).

TABLE 6 Comparison of parameters for opioids Oxy- Oxy- Hydro- Hydro-Parameters codone morphone codone morphone Oral dose 80.0 40.0 80.0 45.5(mg/day) Bioavailability 87% 10% 80% 24% Dose after first 69.6 4.0 64.010.9 pass effect (mg/day) Patch size 140 42 140 40 Required flux* 20.73.97 19.0 11.4 (μg/cm²/h) *Required flux was derived from the followingequation based on daily dose, bioavailability and a theoretical patchsize

${{Required}\mspace{14mu} {Flux}\mspace{14mu} \left( \frac{\mu g}{{cm}^{2} \cdot h} \right)} = {{\frac{{Dose}\mspace{14mu} {\left( \frac{mg}{day} \right){Bioavailability}}\mspace{14mu} (\%)}{{Theoretical}\mspace{14mu} {patch}\mspace{14mu} {size}\mspace{14mu} {\left( {cm}^{2} \right){Time}}\mspace{14mu} \left( \frac{24\mspace{14mu} h}{1{\mspace{11mu} \;}{day}} \right)}1000}\mspace{14mu} \frac{\mu g}{mg}}$${{Oxymorphone}\mspace{14mu} {Required}\mspace{14mu} {Flux}\mspace{14mu} \left( \frac{\mu g}{{cm}^{2} \cdot h} \right)} = {{\frac{40\mspace{14mu} {\left( \frac{mg}{day} \right)10}\mspace{14mu} (\%)}{42\mspace{14mu} {\left( {cm}^{2} \right)\left( \frac{24\mspace{14mu} h}{1\mspace{14mu} {day}} \right)}}1000}\mspace{14mu} \frac{\mu g}{mg}}$${{Oxymorphone}\mspace{14mu} {Required}\mspace{14mu} {Flux}\mspace{14mu} \left( \frac{\mu g}{{cm}^{2} \cdot h} \right)} = {3.97\mspace{14mu} \frac{\mu g}{{cm}^{2} \cdot h}}$

Dual Penetration Enhancer Formulations

Formulations comprising dual penetration enhancers were investigated.Exemplified enhancers included combinations of oleyl alcohol and either(i) oleic acid; (ii) ethyl oleate and (iii) oley oleate. Formulationscomprising dual enhancers include OM-01-043; OM-01-046; OM-01-047 andOM-01-048.

All of the above formulations were cast and flux values were determinedin pig skin and in human skin. The results are summarised in Table 7 andFIGS. 16 and 17. All the exemplified dual penetration enhancerformulations demonstrated marked increases in flux when compared toother exemplified formulations.

TABLE 7 Summary of flux values for formulations OM- 01-043; OM-01-046;OM-01-047 and OM-01-048 Flux Flux Compound (μg/cm²/h) (PIG) (μg/cm²/h)(human) OM-2014-01-043  4.2 ± 1.11 n/a OM-2014-01-046 6.09 ± 1.60 4.674.32 4.37 (65/w/f) (46/b/f) (59/w/f) OM-2014-01-047 6.05 ± 1.12 n/aOM-2014-01-048 5.77 ± 1.10 n/a

Formulation (OM-01-046) was then subsequently tested in three differenttypes of human skin. Three human donor skins were used. All skin donorswere female.

Skin donor one was white; aged 65 years. The flux was determined to be4.67 ug/cm²/hr. The results are shown in FIG. 18.

Skin donor two was black aged 46 years. The flux was determined to be4.32 ug/cm²/hr. The results are shown in FIG. 19.

Skin donor three was white aged 59 years. The flux was determined to be4.37ug/cm²/hr. The results are shown in FIG. 20.

It should be noted that for FIG. 20 there was a leakage in cell 3 at theend of the experiment. Flux values for 64 h and 72 h are artificiallyelevated. Instead of these data points, the average of 48 and 56 hvalues were used for the average flux calculations.

Formulations OM-01-047 and OM-01-048 were also tested on human skin. Theresults are summarised in FIGS. 21 and 22.

Example 2 Abuse-Deterrent Layer Typical Preparation of Abuse-DeterrentFormulations

The following series of steps provide a typical protocol for thepreparation of the naloxone/naltrexone abuse-deterrent formulationsforming part of the invention (in this specific example, the preparationof a 10% 1:1 naloxone base:naloxone·HCl matrix layer). Materials andamounts may vary depending on specific composition of formulations.

Using 12 M (37% HCl, USP) and 200 proof ethanol (USP), prepare a stocksolution of 0.3 M HCl in ethanol.

a. Using a 25 mL volumetric pipet, transfer exactly 25.00 mL of 12 M HClto a 1000 mL volumetric flask and dilute to the mark with 200 proofethanol.

b. Cap the solution and place in the 4° C. refrigerator when not in use.

c. The solution will prepare up to 2 kg of the formulation describedbelow.

Preparation of abuse-deterrent formulation (1 kg batch size):

1. Weigh 100 g (305 mmol) naloxone base into a mixing vessel (10% w/w).

2. Tare weight and add 50 g of polyvinylpyrolidone K30 to the vessel (5%w/w).

3. Pipet 500 mL of 0.3 M HCl (150 mmol) in ethanol into the vessel andbegin blending.

4. Mix until suspension is blended well.

5. Add 1.574 kg Duro-Tak® 9301 (non-volatile content (NVC) 41.3%) (65%w/w).

6. Tare and add 1.333 kg 1:9 hydroxypropylcellulose:ethylcellulose (NVC15%) (20% w/w).

7. Blend until a homogenous suspension is achieved.

8. Extrude at 30 mil wet thickness onto 3M™ Scotchpak™ 9744 releaseliner and air dry for 30 minutes at 25° C.

9. Oven dry at 90° C. for 15 minutes.

10. Laminate with 3M™ Scotchpak™ 9730 backing membrane and reroll thesample until assembly.

11. Store desiccated until ready for use.

Naloxone/Naltrexone Formulations

The composition of exemplary naloxone and naltrexone formulations aresummarized below:

NLX-2014-01-001 10% Naloxone•HCl 20% Ethyl Cellulose:HydroxypropylCellulose (1:9) 70% Dow Corning ® BIO-PSA 7-4302 1000 μL EthanolNLX-2014-01-003 10% Naloxone•HCl 20% Ethyl Cellulose:HydroxypropylCellulose (1:9) 3% Polyvinylpyrollidone [PVP-K30] (MW 30,000) 67% DowCorning ® BIO-PSA 7-4302 1000 μL Ethanol NLX-2014-01-005 10%Naloxone•HCl 20% Ethyl Cellulose:Hydroxypropyl Cellulose (1:9) 5%Polyvinylpyrollidone [PVP-K30] (MW 30,000) 65% Duro-Tak ® 9301 1000 μLEthanol NLX-2014-01-007 10% Naloxone•HCl 20% EthylCellulose:Hydroxypropyl Cellulose (1:9) 7.5% Dow ® Dipropylene GlycolLO+ 62.5% Duro-Tak ® 9301 1000 μL Ethanol NLX-2014-01-009 10%Naloxone•HCl 20% Ethyl Cellulose:Hydroxypropyl Cellulose (1:9) 5% Dow ®Dipropylene Glycol LO+ 65% Duro-Tak ® 900A 500 μL EthanolNLX-2014-01-011 10% Naloxone•HCl 20% Ethyl Cellulose:HydroxypropylCellulose (1:9) 5% Polyvinylpyrollidone [PVP-K30] (MW 30,000) 65%Duro-Tak ® 9301 500 μL Ethanol NTX-2014-01-001 5% Naltrexone•HCl 5%Naltrexone Base 20% Ethyl Cellulose:Hydroxypropyl Cellulose (1:9) 5%Polyvinylpyrollidone [PVP-K30] (MW 30,000) 65% Duro-Tak ® 9301 500 μLEthanol NLX-2014-01-002 Same as 001 with a new batch EC:HPCNLX-2014-01-004 10% Naloxone•HCl 20% Ethyl Cellulose:HydroxypropylCellulose (1:9) 5% Polyvinylpyrollidone [PVP-K30] (MW 30,000) 65% DowCorning ® BIO-PSA 7-4302 1000 μL Ethanol NLX-2014-01-006 10%Naloxone•HCl 20% Ethyl Cellulose:Hydroxypropyl Cellulose (1:9) 5% Dow ®Dipropylene Glycol LO+ 65% Duro-Tak ® 9301 1000 μL EthanolNLX-2014-01-008 10% Naloxone•HCl 20% Ethyl Cellulose:HydroxypropylCellulose (1:9) 5% Dow ® Dipropylene Glycol LO+ 65% Duro-Tak ® 9301 500μL Ethanol NLX-2014-01-010 10% Naloxone•HCl 20% EthylCellulose:Hydroxypropyl Cellulose (1:9) 3% Polyvinylpyrollidone[PVP-K30] (MW 30,000) 67% Duro-Tak ® 9301 500 μL Ethanol NLX-2014-01-0125% Naloxone•HCl 5% Naloxone Base 20% Ethyl Cellulose:HydroxypropylCellulose (1:9) 5% Polyvinylpyrollidone [PVP-K30] (MW 30,000) 65%Duro-Tak ® 9301 1000 μL Ethanol

A variety if adhesive systems, enhancers and cosolvents were employed togenerate different antagonist formulations.

All formulations showed appropriate to excellent dispersion of theantagonist.

Abuse-Deterrent Formulation Test Data

Table 8 below shows molar release ratios of oxymorphone:naltrexone (4:1minimal requirement) from the 5.0% oxymorphone (OM-2014-01-025)prototype abuse deterrent transdermal delivery system (NTX-2014-01-001)in water, ethanol, and acetone. A value less than 4 indicates thatnarcotic blockade would be achieved.

TABLE 8 Molar release ratios of oxymorphone:naltrexone (4:1 minimalrequirement) from the 5.0% oxymorphone (OM-2014-01-025) prototype abusedeterrent transdermal delivery system (NTX-2014-01-001) in water,ethanol, and acetone Time points (min) Water Ethanol Acetone 2 0.4 2.42.4 5 0.3 2.2 1.7 10 0.4 1.9 0.7 20 0.6 1.8 0.6 30 1.7 1.7 0.6 60 0.51.5 0.6

Table 9 below shows molar release ratios of oxymorphone:naltrexone (4:1minimal requirement) from the 5.0% oxymorphone (OM-2014-01-025)prototype abuse deterrent transdermal delivery system (NTX-2014-01-001)under chewing simulation in phosphate buffer pH 6.3

TABLE 9 Molar release ratios of oxymorphone:naltrexone (4:1 minimalrequirement) from the 5.0% oxymorphone (OM-2014-01-025) prototype abusedeterrent transdermal delivery system (NTX-2014-01-001) under chewingsimulation in phosphate buffer pH 6.3 Time points (min) Chewing 1 1.2 21.2 5 1.1 10 1.1 15 1.0

Table 10. Molar release ratios of oxymorphone:naltrexone (4:1 minimalrequirement) from the 3.5% oxymorphone (OM-2014-01-024) prototype abusedeterrent transdermal delivery system (NTX-2014-01-001) in water,ethanol, and acetone

TABLE 10 Molar release ratios of oxymorphone:naltrexone (4:1 minimalrequirement) from the 3.5% oxymorphone (OM-2014-01-024) prototype abusedeterrent transdermal delivery system (NTX-2014-01-001) in water,ethanol, and acetone Time points (min) Water Ethanol Acetone 2 0.3 1.61.6 5 0.2 1.3 0.6 10 0.2 1.2 0.4 20 0.2 1.2 0.4 30 0.3 1.2 0.3 60 0.31.1 0.4

Table 11. Molar release ratios of oxymorphone:naltrexone (4:1 minimalrequirement) from the 3.5% oxymorphone (OM-2014-01-024) prototype abusedeterrent transdermal delivery system (NTX-2014-01-001) under chewingsimulation in phosphate buffer pH 6.3

TABLE 11 Molar release ratios of oxymorphone:naltrexone (4:1 minimalrequirement) from the 3.5% oxymorphone (OM-2014-01-024) prototype abusedeterrent transdermal delivery system (NTX-2014-01-001) under chewingsimulation in phosphate buffer pH 6.3 Time points (min) Chewing 1 0.5 20.6 5 0.5 10 0.4 15 0.4

The ability of abuse-deterrent layer formulations to migrate into theoxymorphone layer was investigated. A placebo oxymorphone layer wasprepared and two abuse-deterrent formulations (NLX-2014-01-011 andNLX-2014-01-012) were tested with different separating layers. Theappearance of both formulations was uniform and aesthetically pleasing.When assembled, no distinguishable layers could be observed and thelayers themselves were inseparable. Patches of size 0.95 cm² patcheswere punched out from the release liner side of the assembled roll. Theresults of the abuse-deterrent permeation studies are presented in Table12 below.

TABLE 12 Permeation of abuse-deterrent formulations into opioid layerCum. Lag Flux Permeation time Formulation μg/cm²/h) (nmol) (h)NLX-2014-01-012 with 0.15 ± 0.07  15.1 ± 5.5  5.4 ± 4.2  cellulosespacing membrane (n = 4) NLX-2014-01-011 with 0.05 ± 0.06* 5.5 ± 6.4*0.3 ± 0.6* cellulose spacing membrane (n = 4) NLX-2014-01-012 with 0.2**12.36** 17.25** Lydall Solupor spacing membrane (n = 3) *Indicates that2 of the four cells analysed showed no permeation of naloxone over 72 hbut were averaged together with the two cells that did have the presenceof naloxone. Overall permeation was miniscule during the 72 h study.**Indicates that two of the three cells have no detection of naloxoneover 72 h diffusion study. The flux, cumulative permeation and lag timevalue shown is from the one cell containing naloxone.

Insofar as NLX-2014-01-011 is concerned, while two cells did showpermeation from the abuse deterrent layer, this was probably due to theabuse deterrent layer contacting the skin, as by the end of theexperiment almost no permeation was observed. It was therefore concludedthat naloxone hydrochloride is largely impermeable in the system. Whenusing a Lydall Solupor 10P05A separator, which is a commerciallyavailable microporous membrane, two of the three cells showed nopermeation whatsoever. The Lydall membrane limited naloxone permeationthrough the skin whereas the same formulation containing 5% naloxonebase and 5% naloxone hydrochloride tested with the cellulose membraneshowed some permeation through all four cells.

Further Abuse Deterrent Studies

Naloxone hydrochloride (NLX) is commonly used to overcome sedation andoverdose of opiate abuse including oxymorphone. In 1990, a study toovercome sedation in dogs showed that a 4.5 mg intravenous dose wasreversed by a 1.2 mg intravenous dose of naloxone (Vet Surg. 1990Sep-Oct;19(5):398-403).

Converting the agonist and antagonist dose to mol amounts providesinformation to calculate a naloxone:oxymorphone ratio required for abusedeterrence. The mol amounts administered in dogs were 3.7 μmol and 14.9μmol of naloxone and oxymorphone, respectively. Thus, the target releaseratio of naloxone:oxymorphone is 1:4.

The formulation to test the abuse deterrent release characteristicscontaining NLX and OXY consisted of formulation OM-2014-01-014, acellulose based polymeric film matrix and a NLX containing matrix asdescribed.

Hydroxyproyl cellulose (HPC) solution was prepared by dissolving 15% ofpolymer (Klucel® EF PH) in ethanol. Another solution of 15% ethylcellulose (EC) was prepared by dissolving the polymer (EC-N50 PH) inchloroform:methanol (8:2). Both solutions were allowed to stir for 24 hto insure complete dissolution in the various solvent systems. Thesestock solutions were used to prepare both the polymeric film layer andNLX containing layer.

A polymeric film that separated the OXY containing layer from the NLXcontaining matrix was prepared by adding 40% w/w polyethylene glycol(PEG) 400 to a 60% mixture of EC:HPC (8:2). The solution was mixedthoroughly, cast onto a release liner at wet thickness of 20 mil, anddried.

The antagonist layer containing NLX was prepared by dispersing 10% w/wNLX in 20% w/w EC:HPC (9:1) and 70% w/w Dow Corning® BIO-PSA 7-4302. Anadditional 0.3 mL/g of ethanol was added to enhance dispersion duringmixing. The solution was cast at 20 mil thickness onto release liner anddried.

OM-2014-01-014 was laminated to the polymeric film containing no drugand the NLX layer laminated to backing membrane ScotchPak™ 9730.Finally, the NLX-backing membrane portion was laminated to the polymericfilm OM-2014-01-014 portion to create a tri-layered abuse deterrentsystem. Patch schematic is shown in FIG. 24.

For the abuse deterrence studies, a 1.0 cm² patch of the abuse deterrentsystem containing 5% OXY and 10% NLX was placed in solvent systemscommonly used to extract opiates under abuse conditions. Each patch wasplaced in a container with 10 mL of water, ethanol, acetone, or pH 6.3phosphate buffer and placed on the orbital shaker. The phosphate bufferwas employed to represent the pH of saliva. A glass rod was used togrind the patch (duration of the study) while in the solution tosimulate chewing. Tables 13 and 14 show the release ratios of NLX:OXYobserved in the abuse media over time.

TABLE 13 Molar release ratios of NLX:OXY from the prototype abusedeterrent transdermal delivery system in water, ethanol, and acetoneTime points (min) Water Ethanol Acetone 2 7.9:1 0.9:1 0.8:1 5 6.1:11.3:1 1.1:1 10 7.4:1 2.0:1 1.8:1 20 10.7:1  1.4:1 1.9:1 30 11.2:1  4.5:11.8:1 60 4.3:1 3.8:1 2.0:1

TABLE 14 Molar release ratios of NLX:OXY from the prototype abusedeterrent transdermal delivery system under chewing simulation inphosphate buffer pH 6.3 Time points (min) Chewing 1 18.1:1 2 17.3:1 525.9:1 10 20.5:1 15 19.5:1

In all abuse media tested the target ratio was achieved initially andthroughout the period of extraction. The ratios observed were muchgreater than the 1:4 NLX:OXY ratio desired in even organic extractionmedia. This observance allows the formulation to be either held at a 10%w/w NLX drug load in the abuse deterrent layer or explore furtherformulations that contain less than 10% drug load and still achieveadequate release ratios that would potentially provide narcoticblockade.

Example 3 Transdermal Patch Patch Assembly

The patch assembly process is a one step process that brings togetherrolls of: 1) an oxymorphone matrix layer attached to a release liner(e.g. 3M™ Scotchpak™ 1022 release liner), 2) Lydall Solupor 10P05Aseparating membrane (commercially purchased with DMF on file) and 3) anabuse-deterrent layer (e.g. a 10% 1:1 naloxone base:naloxone·HCl abusedeterrent layer).

In a fully automated manufacturing process, the three rolls are placedonto a continuous manufacturing platform and then laminated together asshown in FIG. 23. Once laminated, the laminate is then cut to theappropriate size for the dosage form (see FIG. 24) and finally packaged.

Particular embodiments of the invention are described in the followingnumbered paragraphs:

1. A transdermal patch comprising a first layer as defined herein andwherein the opioid analgesic present in said layer is oxymorphone, or apharmaceutically acceptable salt thereof.

2. A transdermal patch according to paragraph 1, wherein the opioidanalgesic is present at an amount of 1-10% w/w.

3. A transdermal patch according to paragraph 2, wherein the opioidanalgesic is present at an amount of 4-7% w/w in said layer.

4. A transdermal patch according to any one of paragraph 1 to 3, whereinthe opioid analgesic is present in a non-salt form, i.e. as a free baseor acid.

5. A transdermal patch according to any one of paragraphs 1 to 4,wherein the total amount of adhesive will constitute between 58 and 99%w/w of the first and second layers respectively.

6. A transdermal patch according to any one of paragraphs 1 to 5,wherein the adhesive is selected from acrylate/polyacrylate materials,rubbers and silicones or mixtures thereof.

7. A transdermal patch according to any one of paragraphs 1 to 6,wherein the adhesive is a mixture of an acrylate/polyacrylate adhesiveand a silicone adhesive.

8. A transdermal patch according to any one of paragraphs 1 to 7,wherein the first layer comprises a penetration enhancer.

9. A transdermal patch according to paragraph 8, wherein the penetrationenhancer is present in an amount of 2-12% w/w of the first layer.

10. A transdermal patch according to paragraph 8 or paragraph 9, whereinthe penetration enhancer is oleic acid.

1. A transdermal patch comprising a multilaminate, said multilaminatecomprising: (i) a first layer comprising an opioid analgesic compound,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable pressure sensitive adhesive; (ii) a second layer comprisingan opioid antagonist, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable adhesive; and (iii) a barrier layerdisposed between the first and second layers, and wherein the barrierlayer substantially prevents the opioid antagonist diffusing from thesecond layer to the first layer during use; and wherein a proportion ofthe opioid antagonist in the second layer is present in the form of apharmaceutically acceptable salt and a proportion of the opioidantagonist is present in a non-salt form (e.g. as a free base).
 2. Atransdermal patch according to claim 1, wherein 5-95% w/w or 30-70% w/wof the total opioid antagonist present in the second layer is in theform of a pharmaceutically acceptable salt and the remainder is in anon-salt (e.g. free base) form.
 3. (canceled)
 4. A transdermal patchcomprising a multilaminate, said multilaminate comprising: (i) a firstlayer comprising an opioid analgesic compound as defined hereinbefore,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable pressure sensitive adhesive; (ii) a second layer comprisingan opioid antagonist, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable adhesive as defined hereinbefore; and(iii) a barrier layer disposed between the first and second layers, andwherein the barrier layer substantially prevents the opioid antagonistdiffusing from the second layer to the first layer during use; whereinsaid barrier layer comprises a material selected from the groupconsisting of polyethylene, ethylene vinyl acetate, polypropylene,polyurethane, polyvinyl acetate, polyvinylidene chloride, polyester,polyethylene terephthalate, polybutylene terephthalate, rayon (synthetictextile fibres produced by forcing cellulose through fine spinnerets andsolidifying the resultant filaments), wood pulp, and spun-lacedpolyester.
 5. A transdermal patch according to claim 4, wherein theopioid analgesic is selected from morphine, codeine, thebaine,diacetylmorphine (morphine diacetate; heroin), nicomorphine (morphinedinicotinate), dipropanoylmorphine (morphine dipropionate),desomorphine, acetylpropionylmorphine, dibenzoylmorphine,diacetyldihydromorphine, hydromorphone, hydrocodone, oxycodone,oxymorphone, ethylmorphine and buprenorphine, fentanyl, pethidine,levorphanol, methadone, tramadol and dextropropoxyphene.
 6. Atransdermal patch according to claim 4, wherein the opioid analgesic isoxymorphone, or a pharmaceutically acceptable salt thereof.
 7. Atransdermal patch according to claim 4, wherein the opioid analgesic ispresent at an amount of 1-10% w/w or 4-7% w/w in the first layer. 8.(canceled)
 9. A transdermal patch according to claim 4, wherein theopioid analgesic is present in a non-salt form, i.e. as a free base oracid.
 10. A transdermal patch according to claim 4, wherein the totalamount of adhesive will constitute between 58 and 99% w/w of the firstand second layers respectively.
 11. A transdermal patch according toclaim 4, wherein the adhesive is selected from acrylate/polyacrylatematerials, rubbers and silicones or mixtures thereof.
 12. A transdermalpatch according to claim 4, wherein the adhesive is a mixture of anacrylate/polyacrylate adhesive and a silicone adhesive.
 13. Atransdermal patch according claim 4, wherein the first layer comprises apenetration enhancer.
 14. A transdermal patch according to claim 13,wherein the penetration enhancer is present in an amount of 2-12% w/w ofthe first layer.
 15. A transdermal patch according to claim 13, whereinthe penetration enhancer is oleic acid.
 16. A transdermal patchaccording to claim 4, wherein the opioid antagonist in the second layeris selected from naltrexone (“NTX”), naloxone (“NLX”) or nalmefene. 17.A transdermal patch according to claim 4, wherein the opioid antagonistis present in an amount of 1-20% w/w of the second layer.
 18. Atransdermal patch according to claim 4, wherein the second layer furthercomprises polyvinylpyrollidinone (e.g. polyvinylpyrollidone K30) in anamount of 0.5 to 15% w/w of the second layer.
 19. A transdermal patchaccording to claim 4, wherein the second layer further comprises acellulose component in an amount of 5 to 25% w/w of the second layer.20. A transdermal patch according to claim 4, wherein the second layerfurther comprises a hydrophilic material (e.g. propylene glycol ordipropylene glycol) in an amount of 1 to 10% w/w of the second layer.21. A transdermal patch according to claim 4, wherein the barrier layeris a microporous ultra high density polyethylene (UHDPE) material (e.g.Solupor® manufactured by DSM Desotech, Denmark).
 22. A transdermal patchaccording to claim 4, wherein the barrier layer is an ethylene vinylacetate (EVA) membranes. 23.-24. (canceled)
 25. A method of treating acondition selected form the group consisting of opioid dependence,alcohol dependence, polydrug addiction, pain, cocaine addiction, eatingdisorders (e.g., binge eating) and treatment-resistant depression in asubject in need of such treatment, said method comprising administeringa transdermal patch according to claim 4 to the skin of the subject.